Serine/threonine kinase inhibitors

ABSTRACT

Compounds of Formula I or a stereoisomer, tautomer, prodrug or pharmaceutically acceptable salt thereof are provided, which are useful for the treatment of hyperproliferative, pain and inflammatory diseases. Methods of using compounds of Formula I or a stereoisomer, tautomer, prodrug or pharmaceutically acceptable salt thereof, for in vitro, in situ, and in vivo diagnosis, prevention or treatment of such disorders in mammalian cells, or associated pathological conditions are disclosed.

RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.14/181,418 filed on Feb. 14, 2014, which is a divisional of U.S. patentapplication Ser. No. 13/782,513 filed on Mar. 1, 2013, and issued asU.S. Pat. No. 8,697,715 on Apr. 15, 2014, which claims priority to U.S.Provisional Application No. 61/605,523 filed on Mar. 1, 2012. The entirecontent of these applications is hereby incorporated herein byreference.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to compounds that inhibit serine/threoninekinases and are useful for treating hyperproliferative and neoplasticdiseases by inhibiting signal transduction pathways, which are commonlyoveractive or overexpressed in cancerous tissue. The present compoundsare selective inhibitors of ERK (extracellular-signal regulated kinase).The present invention further relates to methods for treating cancer orhyperproliferative diseases with compounds of the present invention.

2. Description of the State of the Art

The processes involved in tumor growth, progression, and metastasis aremediated by signaling pathways that are activated in cancer cells. TheERK pathway plays a central role in regulating mammalian cell growth byrelaying extracellular signals from ligand-bound cell surface receptortyrosine kinase (“RTK's”), such as ErbB family, PDGF, FGF, and VEGFreceptor tyrosine kinase. Activation of an RTK induces a cascade ofphosphorylation events that begins with activation of Ras. Activation ofRas leads to the recruitment and activation of Raf, a serine-threoninekinase. Activated Raf then phosphorylates and activates MEK1/2, whichthen phosphorylates and activates ERK1/2. When activated, ERK1/2phosphorylates several downstream targets involved in a multitude ofcellular events, including cytoskeletal changes and transcriptionalactivation. The ERK/MAPK pathway is one of the most important for cellproliferation, and it is believed that the ERK/MAPK pathway isfrequently activated in many tumors. Ras genes, which are upstream ofERK1/2, are mutated in several cancers, including colorectal, melanoma,breast and pancreatic tumors. The high Ras activity is accompanied byelevated ERK activity in many human tumors. In addition, mutations ofBRAF, a serine-threonine kinase of the Raf family, are associated withincreased kinase activity. Mutations in BRAF have been identified inmelanomas (60%), thyroid cancers (greater than 40%) and colorectalcancers. These observations indicate that the ERK1/2 signaling pathwayis an attractive pathway for anti-cancer therapies in a broad spectrumof human tumors (Kohno, M. and J. Pouyssegur. “Pharmacologicalinhibitors of the ERK signaling pathway: application as anticancerdrugs.” Prog. Cell Cycle Res. Vol. 5 (2003): pp. 219-224).

The ERK pathway has also been cited as a promising therapeutic targetfor the treatment of pain and inflammation (Ma, Weiya and Remi Quirion.“The ERK/MAPK pathway, as a target for the treatment of neuropathicpain.” Expert Opin. Ther. Targets. 9(4) (2005): pp. 699-713; and Sommer,Claudia and Frank Birklein. “Resolvins and inflammatory pain.” F1000Medicine Reports. 3:19 (2011)).

Therefore, small-molecular inhibitors of ERK activity (i.e., ERK1 and/orERK2 activity) would be useful for treating a broad spectrum of cancers,such as, for example, melanoma, pancreatic cancer, thyroid cancer,colorectal cancer, lung cancer, breast cancer, and ovarian cancer, aswell as a treatment for pain and inflammation, such as arthritis, lowback pain, inflammatory bowel disease, and rheumatism. Such acontribution is provided herein.

SUMMARY OF THE INVENTION

There is a continuing need for new and novel therapeutic agents that canbe used for cancer and hyperproliferative conditions. The Raf/MEK/ERKpathway is an important signaling pathway, which is frequentlyoverexpressed and/or overactive in many cancerous tissues. Design anddevelopment of new pharmaceutical compounds is essential.

More specifically, one aspect provides compounds of Formula I:

or a stereoisomer, tautomer, prodrug or pharmaceutically acceptable saltthereof, wherein X₁, X₂, Y₁, Y₂, R¹, R², R³ and R⁴ are as definedherein.

Another aspect provides compounds of Formulas II, III, IV, V, VI, VII,VIII, IX and X, or a stereoisomer, tautomer or pharmaceuticallyacceptable salt thereof.

Another aspect provides a method for treating a hyperproliferativedisorder by administering a therapeutically effective quantity of acompound according to Formula I, II, III, IV, V, VI, VII, VIII, IX or X,or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof,to a patient in need thereof. The compound can be administered alone orco-administered with at least one other anti-hyperproliferative orchemotherapeutic compound.

Another aspect provides a method of inhibiting ERK protein kinaseactivity in a cell comprising treating the cell with a compoundaccording to Formula I, II, III, IV, V, VI, VII, VIII, IX or X, or astereoisomer, tautomer or pharmaceutically acceptable salt thereof, inan amount effective to attenuate or eliminate ERK kinase activity.

Another aspect provides methods of treating or preventing a disease ordisorder modulated by ERK, comprising administering to a mammal in needof such treatment an effective amount of a compound of Formula I, II,III, IV, V, VI, VII, VIII, IX or X, or a stereoisomer, tautomer orpharmaceutically acceptable salt thereof. Examples of such diseases anddisorders include, but are not limited to, hyperproliferative disorders,such as cancer.

Another aspect provides methods of treating or preventing cancer,comprising administering to a mammal in need of such treatment aneffective amount of a compound of Formula I, II, III, IV, V, VI, VII,VIII, IX or X, or a stereoisomer, tautomer or pharmaceuticallyacceptable salt thereof, alone or in combination with one or moreadditional compounds having anti-cancer properties.

Another aspect provides a method of treating a hyperproliferativedisease in a mammal comprising administering a therapeutically effectiveamount of a compound of Formula I, II, III, IV, V, VI, VII, VIII, IX orX, or a stereoisomer, tautomer or pharmaceutically acceptable saltthereof, to the mammal.

Another aspect provides the use of a compound of Formula I, II, III, IV,V, VI, VII, VIII, IX or X, or a stereoisomer, tautomer orpharmaceutically acceptable salt thereof, in the manufacture of amedicament for the treatment of a hyperproliferative disease.

Another aspect provides a compound of Formula I, II, III, IV, V, VI,VII, VIII, IX or X, or a stereoisomer, tautomer or pharmaceuticallyacceptable salt thereof, for use in the treatment of hyperproliferativediseases.

Another aspect provides a pharmaceutical composition comprising acompound of Formula I, II, III, IV, V, VI, VII, VIII, IX or X, or astereoisomer, tautomer or pharmaceutically acceptable salt thereof, anda pharmaceutically acceptable carrier, diluent or excipient.

Another aspect provides intermediates for preparing compounds of FormulaI, II, III, IV, V, VI, VII, VIII, IX or X. Certain compounds of theFormulas may be used as intermediates for other compounds of theFormulas.

Another aspect includes processes for preparing, methods of separation,and methods of purification of the compounds described herein.

DETAILED DESCRIPTION OF THE INVENTION

Reference will now be made in detail to certain embodiments, examples ofwhich are illustrated in the accompanying structures and formulas. Whileenumerated embodiments will be described, it will be understood thatthey are not intended to limit the invention to those embodiments. Onthe contrary, the invention is intended to cover all alternatives,modifications, and equivalents, which may be included within the scopeof the present invention as defined by the claims. One skilled in theart will recognize many methods and materials similar or equivalent tothose described herein, which could be used in the practice of thepresent invention. The present invention is in no way limited to themethods and materials described. In the event that one or more of theincorporated literature and similar materials differs from orcontradicts this application, including but not limited to definedterms, term usage, described techniques, or the like, this applicationcontrols.

DEFINITIONS

The phrase “a” or “an” entity as used herein refers to one or more ofthat entity; for example, a compound refers to one or more compounds orat least one compound. As such, the terms “a” (or “an”), “one or more”,and “at least one” can be used interchangeably herein.

The phrase “as defined herein” refers to the broadest definition foreach group as provided in the Detailed Description of the Invention orthe broadest claim. In all other embodiments provided below,substituents that can be present in each embodiment, and which are notexplicitly defined, retain the broadest definition provided in theDetailed Description of the Invention.

As used in this specification, whether in a transitional phrase or inthe body of the claim, the terms “comprise(s)” and “comprising” are tobe interpreted as having an open-ended meaning. That is, the terms areto be interpreted synonymously with the phrases “having at least” or“including at least”. When used in the context of a process, the term“comprising” means that the process includes at least the recited steps,but may include additional steps. When used in the context of a compoundor composition, the term “comprising” means that the compound orcomposition includes at least the recited features or components, butmay also include additional features or components. Additionally, thewords “include,” “including,” and “includes” when used in thisspecification and in the following claims are intended to specify thepresence of stated features, integers, components, or steps, but they donot preclude the presence or addition of one or more other features,integers, components, steps, or groups thereof.

The term “independently” is used herein to indicate that a variable isapplied in any one instance without regard to the presence or absence ofa variable having that same or a different definition within the samecompound. Thus, in a compound in which R″ appears twice and is definedas “independently carbon or nitrogen”, both R″s can be carbon, both R″scan be nitrogen, or one R″ can be carbon and the other nitrogen.

When any variable (e.g., R¹, R^(4a), Ar, X₁ or Het) occurs more than onetime in any moiety or formula depicting and describing compoundsemployed or claimed in the present invention, its definition on eachoccurrence is independent of its definition at every other occurrence.Also, combinations of substituents and/or variables are permissible onlyif such compounds result in stable compounds.

The term “optional” or “optionally” as used herein means that asubsequently described event or circumstance may, but need not, occur,and that the description includes instances where the event orcircumstance occurs and instances in which it does not. For example,“optionally substituted” means that the optionally substituted moietymay incorporate a hydrogen or a substituent.

The term “about” is used herein to mean approximately, in the region of,roughly, or around. When the term “about” is used in conjunction with anumerical range, it modifies that range by extending the boundariesabove and below the numerical values set forth. In general, the term“about” is used herein to modify a numerical value above and below thestated value by a variance of 20%.

As used herein, the recitation of a numerical range for a variable isintended to convey that the invention may be practiced with the variableequal to any of the values within that range. Thus, for a variable thatis inherently discrete, the variable can be equal to any integer valueof the numerical range, including the end-points of the range.Similarly, for a variable that is inherently continuous, the variablecan be equal to any real value of the numerical range, including theend-points of the range. As an example, a variable that is described ashaving values between 0 and 2, can be 0, 1 or 2 for variables that areinherently discrete, and can be 0.0, 0.1, 0.01, 0.001, or any other realvalue for variables that are inherently continuous.

Compounds of Formula I exhibit tautomerism. Tautomeric compounds canexist as two or more interconvertable species. Prototropic tautomersresult from the migration of a covalently bonded hydrogen atom betweentwo atoms. Tautomers generally exist in equilibrium and attempts toisolate an individual tautomers usually produce a mixture whose chemicaland physical properties are consistent with a mixture of compounds. Theposition of the equilibrium is dependent on chemical features within themolecule. For example, in many aliphatic aldehydes and ketones, such asacetaldehyde, the keto form predominates; while in phenols, the enolform predominates. Common prototropic tautomers include keto/enol(—C(═O)—CH₂—

—C(—OH)═CH—), amide/imidic acid (—C(═O)—NH—

—C(—OH)═N—) and amidine (—C(═NR)—NH—

—C(—NHR)═N—) tautomers. The latter two are particularly common inheteroaryl and heterocyclic rigs, and the present invention encompassesall tautomeric forms of the compounds.

It will be appreciated by the skilled artisan that some of the compoundsof Formula I may contain one or more chiral centers and therefore existin two or more stereoisomeric forms. The racemates of these isomers, theindividual isomers and mixtures enriched in one enantiomer, as well asdiastereomers when there are two chiral centers, and mixtures partiallyenriched with specific diastereomers are within the scope of the presentinvention. The present invention includes all the individualstereoisomers (e.g., enantiomers), racemic mixtures or partiallyresolved mixtures of the compounds of Formula I and, where appropriate,the individual tautomeric forms thereof.

The compounds of Formula I may contain a basic center and suitable acidaddition salts are formed from acids that form non-toxic salts. Examplesof salts of inorganic acids include the hydrochloride, hydrobromide,hydroiodide, chloride, bromide, iodide, sulfate, bisulfate, nitrate,phosphate, and hydrogen phosphate. Examples of salts of organic acidsinclude acetate, fumarate, pamoate, aspartate, besylate, carbonate,bicarbonate, camsylate, D and L-lactate, D and L-tartrate, esylate,mesylate, malonate, orotate, gluceptate, methylsulfate, stearate,glucuronate, 2-napsylate, tosylate, hibenzate, nicotinate, isethionate,malate, maleate, citrate, gluconate, succinate, saccharate, benzoate,esylate, and pamoate salts. For a review on suitable salts, see Berge,Stephen M., et al. “Pharmaceutical salts.” J. Pharm. Sci. Vol. 66, No. 1(1977): 1-19, and Paulekuhn, G. Steffen, et al. “Trends in ActivePharmaceutical Ingredient Salt Selection based on Analysis of the OrangeBook Database.” J. Med. Chem. Vol. 50, No. 26 (2007): 6665-6672.

Technical and scientific terms used herein have the meaning commonlyunderstood by one of skill in the art to which the present inventionpertains, unless otherwise defined. Reference is made herein to variousmethodologies and materials known to those of skill in the art. Astandard reference work setting forth the general principles ofpharmacology include Hardman, Joel Griffith, et al. Goodman & Gilman'sThe Pharmacological Basis of Therapeutics. New York: McGraw-HillProfessional, 2001. The starting materials and reagents used inpreparing these compounds generally are either available from commercialsuppliers, such as Sigma-Aldrich (St. Louis, Mo.), or are prepared bymethods known to those skilled in the art following procedures set forthin references. Materials, reagents and the like to which reference aremade in the following description and examples are obtainable fromcommercial sources, unless otherwise noted. General synthetic procedureshave been described in treatises, such as Louis F. Fieser and MaryFieser, Reagents for Organic Synthesis. v. 1-23, New York: Wiley1967-2006 ed. (also available via the Wiley InterScience® website);LaRock, Richard C., Comprehensive Organic Transformations: A Guide toFunctional Group Preparations. New York: Wiley-VCH, 1999; B. Trost andI. Fleming, eds. Comprehensive Organic Synthesis. v. 1-9, Oxford:Pergamon 1991; A. R. Katritzky and C. W. Rees, eds. ComprehensiveHeterocyclic Chemistry. Oxford: Pergamon 1984; A. R. Katritzky and C. W.Rees, eds. Comprehensive Heterocyclic Chemistry II. Oxford: Pergamon1996; and Paquette, Leo A., ed. Organic Reactions. v. 1-40, New York:Wiley & Sons 1991; and will be familiar to those skilled in the art.

The term “alkyl” includes linear or branched-chain radicals of carbonatoms. Some alkyl moieties have been abbreviated, for example, methyl(“Me”), ethyl (“Et”), propyl (“Pr”) and butyl (“Bu”), and furtherabbreviations are used to designate specific isomers of compounds, forexample, 1-propyl or n-propyl (“n-Pr”), 2-propyl or isopropyl (“i-Pr”),1-butyl or n-butyl (“n-Bu”), 2-methyl-1-propyl or isobutyl (“i-Bu”),1-methylpropyl or s-butyl (“s-Bu”), 1,1-dimethylethyl or t-butyl(“t-Bu”) and the like. The abbreviations are sometimes used inconjunction with elemental abbreviations and chemical structures, forexample, methanol (“MeOH”) or ethanol (“EtOH”). In certain embodiments,alkyl is C₁₋₁₀ alkyl. In certain embodiments, alkyl is C₁₋₆ alkyl.

Additional abbreviations used throughout the application may include,for example, benzyl (“Bn”), phenyl (“Ph”), acetate (“Ac”) and mesylate(“Ms”).

The terms “alkenyl” and “alkynyl” also include linear or branched-chainradicals of carbon atoms.

The terms “heterocycle” and “heterocyclic” include four to sevenmembered saturated or partially unsaturated rings containing one, two orthree heteroatoms selected from the group consisting of O, N, S, S(═O)and S(═O)₂. In certain instances, these terms may be specificallyfurther limited, such as, “five to six membered heterocyclic” onlyincluding five and six membered rings.

The term “heteroaryl” includes five to six membered aromatic ringscontaining one, two, three or four heteroatoms selected from the groupconsisting of O, N and S. In certain instances, these terms may bespecifically further limited, such as, five to six membered heteroaryl,wherein the heteroaryl contains one or two nitrogen heteroatoms. As wellknown to those skilled in the art, heteroaryl rings have less aromaticcharacter than their all-carbon counter parts. Thus, for the purposes ofthe invention, a heteroaryl group need only have some degree of aromaticcharacter.

A bond drawn into ring system (as opposed to connected at a distinctvertex) indicates that the bond may be attached to any of the suitablering atoms.

The terms “treat” or “treatment” refer to therapeutic, prophylactic,palliative or preventative measures. Beneficial or desired clinicalresults include, but are not limited to, alleviation of symptoms,diminishment of extent of disease, stabilized (i.e., not worsening)state of disease, delay or slowing of disease progression, ameliorationor palliation of the disease state, and remission (whether partial ortotal), whether detectable or undetectable. “Treatment” can also meanprolonging survival as compared to expected survival if not receivingtreatment. Those in need of treatment include those already with thecondition or disorder, as well as those prone to have the condition ordisorder or those in which the condition or disorder is to be prevented.

The phrases “therapeutically effective amount” or “effective amount”mean an amount of a compound described herein that, when administered toa mammal in need of such treatment, sufficient to (i) treat or preventthe particular disease, condition, or disorder, (ii) attenuate,ameliorate, or eliminate one or more symptoms of the particular disease,condition, or disorder, or (iii) prevent or delay the onset of one ormore symptoms of the particular disease, condition, or disorderdescribed herein. The amount of a compound that will correspond to suchan amount will vary depending upon factors such as the particularcompound, disease condition and its severity, the identity (e.g.,weight) of the mammal in need of treatment, but can nevertheless beroutinely determined by one skilled in the art.

The terms “cancer” and “cancerous” refer to or describe thephysiological condition in mammals that is typically characterized byabnormal or unregulated cell growth. A “tumor” comprises one or morecancerous cells. Examples of cancer include, but are not limited to,carcinoma, lymphoma, blastoma, sarcoma, and leukemia or lymphoidmalignancies. More particular examples of such cancers include squamouscell cancer (e.g., epithelial squamous cell cancer), lung cancerincluding small cell lung cancer, non-small cell lung cancer (“NSCLC”),adenocarcinoma of the lung and squamous carcinoma of the lung, cancer ofthe peritoneum, hepatocellular cancer, gastric or stomach cancerincluding gastrointestinal cancer, pancreatic cancer, glioblastoma,cervical cancer, ovarian cancer, liver cancer, bladder cancer, hepatoma,breast cancer, colon cancer, rectal cancer, colorectal cancer,endometrial or uterine carcinoma, salivary gland carcinoma, kidney orrenal cancer, prostate cancer, vulval cancer, thyroid cancer, hepaticcarcinoma, anal carcinoma, penile carcinoma, skin cancer, includingmelanoma, as well as head and neck cancer.

A “chemotherapeutic agent” is a chemical compound useful in thetreatment of cancer. Examples of chemotherapeutic agents includeerlotinib (TARCEVA®, Genentech/OSI Pharm.), bortezomib (VELCADE®,Millennium Pharm.), fulvestrant (FASLODEX®, AstraZeneca), sunitib(SUTENT®, Pfizer/Sugen), letrozole (FEMARA®, Novartis), imatinibmesylate (GLEEVEC®, Novartis), finasunate (VATALANIB®, Novartis),oxaliplatin (ELOXATIN®, Sanofi), 5-FU (5-fluorouracil), leucovorin,Rapamycin (Sirolimus, RAPAMUNE®, Wyeth), Lapatinib (TYKERB®, GSK572016,Glaxo Smith Kline), Lonafamib (SCH 66336), sorafenib (NEXAVAR®, BayerLabs), gefitinib (IRESSA®, AstraZeneca), AG1478, alkylating agents suchas thiotepa and CYTOXAN® cyclosphosphamide; alkyl sulfonates such asbusulfan, improsulfan and piposulfan; aziridines such as benzodopa,carboquone, meturedopa, and uredopa; ethylenimines and methylamelaminesincluding altretamine, triethylenemelamine, triethylenephosphoramide,triethylenethiophosphoramide and trimethylomelamine; acetogenins(especially bullatacin and bullatacinone); a camptothecin (including thesynthetic analog topotecan); bryostatin; callystatin; CC-1065 (includingits adozelesin, carzelesin and bizelesin synthetic analogs);cryptophycins (particularly cryptophycin 1 and cryptophycin 8);dolastatin; duocarmycin (including the synthetic analogs, KW-2189 andCB1-TM1); eleutherobin; pancratistatin; a sarcodictyin; spongistatin;nitrogen mustards such as chlorambucil, chlomaphazine,chlorophosphamide, estramustine, ifosfamide, mechlorethamine,mechlorethamine oxide hydrochloride, melphalan, novembichin,phenesterine, prednimustine, trofosfamide, uracil mustard; nitrosoureassuch as carmustine, chlorozotocin, fotemustine, lomustine, nimustine,and ranimnustine; antibiotics such as the enediyne antibiotics (e.g.,calicheamicin, especially calicheamicin γ1I and calicheamicin ω1I (AngewChem. Intl. Ed. Engl. 1994 33:183-186); dynemicin, including dynemicinA; bisphosphonates, such as clodronate; an esperamicin; as well asneocarzinostatin chromophore and related chromoprotein enediyneantibiotic chromophores), aclacinomysins, actinomycin, authramycin,azaserine, bleomycins, cactinomycin, carabicin, caminomycin,carzinophilin, chromomycinis, dactinomycin, daunorubicin, detorubicin,6-diazo-5-oxo-L-norleucine, ADRIAMYCIN® (doxorubicin),morpholino-doxorubicin, cyanomorpholino-doxorubicin,2-pyrrolino-doxorubicin and deoxydoxorubicin), epirubicin, esorubicin,idarubicin, marcellomycin, mitomycins such as mitomycin C, mycophenolicacid, nogalamycin, olivomycins, peplomycin, porfiromycin, puromycin,quelamycin, rodorubicin, streptonigrin, streptozocin, tubercidin,ubenimex, zinostatin, zorubicin; anti-metabolites such as methotrexateand 5-fluorouracil (5-FU); folic acid analogs such as denopterin,methotrexate, pteropterin, trimetrexate; purine analogs such asfludarabine, 6-mercaptopurine, thiamiprine, thioguanine; pyrimidineanalogs such as ancitabine, azacitidine, 6-azauridine, carmofur,cytarabine, dideoxyuridine, doxifluridine, enocitabine, floxuridine;androgens such as calusterone, dromostanolone propionate, epitiostanol,mepitiostane, testolactone; anti-adrenals such as aminoglutethimide,mitotane, trilostane; folic acid replenisher such as frolinic acid;aceglatone; aldophosphamide glycoside; aminolevulinic acid; eniluracil;amsacrine; bestrabucil; bisantrene; edatraxate; defofamine; demecolcine;diaziquone; elfomithine; elliptinium acetate; an epothilone; etoglucid;gallium nitrate; hydroxyurea; lentinan; lonidainine; maytansinoids suchas maytansine and ansamitocins; mitoguazone; mitoxantrone; mopidamnol;nitraerine; pentostatin; phenamet; pirarubicin; losoxantrone;podophyllinic acid; 2-ethylhydrazide; procarbazine; PSK® polysaccharidecomplex (JHS Natural Products, Eugene, Oreg.); razoxane; rhizoxin;sizofuran; spirogermanium; tenuazonic acid; triaziquone;2,2′,2″-trichlorotriethylamine; trichothecenes (especially T-2 toxin,verracurin A, roridin A and anguidine); urethan; vindesine; dacarbazine;mannomustine; mitobronitol; mitolactol; pipobroman; gacytosine;arabinoside (“Ara-C”); cyclophosphamide; thiotepa; taxoids, e.g., TAXOL(paclitaxel; Bristol-Myers Squibb Oncology, Princeton, N.J.), ABRAXANE®(Cremophor-free), albumin-engineered nanoparticle formulations ofpaclitaxel (American Pharmaceutical Partners, Schaumberg, Ill.), andTAXOTERE® (docetaxel, doxetaxel; Sanofi-Aventis); chlorambucil; GEMZAR®(gemcitabine); 6-thioguanine; mercaptopurine; methotrexate; platinumanalogs such as cisplatin and carboplatin; vinblastine; etoposide(VP-16); ifosfamide; mitoxantrone; vincristine; NAVELBINE®(vinorelbine); novantrone; teniposide; edatrexate; daunomycin;aminopterin; capecitabine (XELODA®); ibandronate; CPT-11; topoisomeraseinhibitor RFS 2000; difluoromethylomithine (DMFO); retinoids such asretinoic acid; and pharmaceutically acceptable salts, acids andderivatives of any of the above.

Also included in the definition of “chemotherapeutic agent” are: (i)anti-hormonal agents that act to regulate or inhibit hormone action ontumors, such as anti-estrogens and selective estrogen receptormodulators (SERMs), including, for example, tamoxifen (includingNOLVADEX®; tamoxifen citrate), raloxifene, droloxifene,4-hydroxytamoxifen, trioxifene, keoxifene, LY117018, onapristone, andFARESTON® (toremifine citrate); (ii) aromatase inhibitors that inhibitthe enzyme aromatase, which regulates estrogen production in the adrenalglands, such as, for example, 4(5)-imidazoles, aminoglutethimide,MEGASE® (megestrol acetate), AROMASIN® (exemestane; Pfizer),formestanie, fadrozole, RIVISOR® (vorozole), FEMARA® (letrozole;Novartis), and ARIMIDEX® (anastrozole; AstraZeneca); (iii)anti-androgens, such as flutamide, nilutamide, bicalutamide, leuprolide,and goserelin; as well as troxacitabine (a 1,3-dioxolane nucleosidecytosine analog); (iv) protein kinase inhibitors; (v) lipid kinaseinhibitors; (vi) antisense oligonucleotides, particularly those whichinhibit expression of genes in signaling pathways implicated in aberrantcell proliferation, such as, for example, PKC-alpha, Raf and H-Ras;(vii) ribozymes such as VEGF expression inhibitors (e.g., ANGIOZYME®)and HER2 expression inhibitors; (viii) vaccines such as gene therapyvaccines, for example, ALLOVECTIN®, LEUVECTIN®, and VAXID®; PROLEUKIN®,rIL-2; a topoisomerase 1 inhibitor such as LURTOTECAN®; ABARELIX® rmRH;(ix) anti-angiogenic agents such as bevacizumab (AVASTIN®, Genentech);and (x) pharmaceutically acceptable salts, acids and derivatives of anyof the above.

The phrase “pharmaceutically acceptable” indicates that the substance orcomposition is compatible chemically and/or toxicologically, with theother ingredients comprising a formulation, and/or the mammal beingtreated therewith.

The phrase “pharmaceutically acceptable salt,” as used herein, refers topharmaceutically acceptable organic or inorganic salts of a compounddescribed herein.

The compounds described herein also include other salts of suchcompounds that are not necessarily pharmaceutically acceptable salts,and which may be useful as intermediates for preparing and/or purifyingcompounds described herein and/or for separating enantiomers ofcompounds described herein.

The term “mammal” means a warm-blooded animal that has or is at risk ofdeveloping a disease described herein and includes, but is not limitedto, guinea pigs, dogs, cats, rats, mice, hamsters, and primates,including humans.

The term “prodrug” as used in this application refers to a precursor orderivative form of a compound of Formula I that is less active orinactive compared to the parent compound or drug and is capable of beingmetabolized in vivo into the more active parent form. See, e.g., Wilman,D E. “Prodrugs in Cancer Chemotherapy.” Biochem. Soc. Trans. Vol. 14,No. 2 (1986): pp. 375-382; and Stella, Valentino J. and Kenneth J.Himmelstein. “Prodrugs: A Chemical Approach to Targeted Drug Delivery.”In Directed Drug Delivery. Borchardt, Ronald T., Arnold J. Repta andValentino J. Stella, eds. University of Michigan: Humana Press 1985, pp.247-267. The prodrugs of this invention include, but are not limited to,phosphate-containing prodrugs, thiophosphate-containing prodrugs,sulfate-containing prodrugs, peptide-containing prodrugs, D-aminoacid-modified prodrugs, glycosylated prodrugs, β-lactam-containingprodrugs, optionally substituted phenoxyacetamide-containing prodrugs,optionally substituted phenylacetamide-containing prodrugs,5-fluorocytosine and other 5-fluorouridine prodrugs which can beconverted into the more active cytotoxic free drug.

ERK Inhibitors

Provided herein are compounds, and pharmaceutical formulations thereof,that are potentially useful in the treatment of diseases, conditionsand/or disorders modulated by ERK.

One embodiment provides compounds of Formula I:

or a stereoisomer, tautomer, prodrug or pharmaceutically acceptable saltthereof, wherein:

X₁ is selected from CH and N;

X₂ is selected from CR⁵ and N;

Y₁ is selected from CR⁶ and N;

Y₂ is selected from CR⁷ and N;

R¹ is selected from (a) C₁-C₆ alkyl optionally substituted with one ormore groups independently selected from halogen, OR^(a), NR^(b)R^(c),oxo, CN, C₃-C₆ cycloalkyl and a 3 to 7 membered heterocycle, (b) C₃-C₇cycloalkyl optionally substituted with one or more groups independentlyselected from halogen, OR^(a), CN and C₁-C₃ alkyl optionally substitutedwith one or more groups independently selected from halogen and OR^(d),(c) phenyl optionally substituted with one or more groups independentlyselected from halogen, OR^(a), CN, C₃-C₆ cycloalkyl and C₁-C₃ alkyloptionally substituted with one or more groups independently selectedfrom halogen and OR^(d), (d) a 3 to 7 membered saturated or partiallyunsaturated heterocycle optionally substituted with one or more groupsindependently selected from halogen, OR^(a), oxo, CN, C₃-C₆ cycloalkyland C₁-C₃ alkyl optionally substituted with one or more groupsindependently selected from halogen and OR^(d), (e) a 5 to 6 memberedheteroaryl optionally substituted with one or more groups independentlyselected from halogen, OR^(e), oxide, CN, C₃-C₆ cycloalkyl and C₁-C₃alkyl optionally substituted with one or more groups independentlyselected from halogen, oxo and OR^(d), and (f) a 7 to 10 memberedbicyclic heterocycle optionally substituted with one or more groupsindependently selected from halogen, OR^(a), oxo, CN, C₃-C₆ cycloalkyland C₁-C₃ alkyl optionally substituted with one or more groupsindependently selected from halogen and OR^(d);

R² is selected from (a) hydrogen, (b) C₁-C₆ alkyl optionally substitutedwith one or more groups selected from OR^(f), oxo, NH₂, NH(C₁-C₃ alkyl)and N(C₁-C₃ alkyl)₂, (c) C₁-C₆ alkenyl optionally substituted with oneor more groups selected from OR^(f), oxo, NH₂, NH(C₁-C₃ alkyl) andN(C₁-C₃ alkyl)₂, (d) C₁-C₆ alkynyl optionally substituted with one ormore groups selected from OR^(f), oxo, NH₂, NH(C₁-C₃ alkyl) and N(C₁-C₃alkyl)₂, (e) C₃-C₆ cycloalkyl optionally substituted with one or moregroups selected from OR^(f) and R⁵, (f) phenyl optionally substitutedwith one or more groups selected from OR^(f) and R^(g), (g) a 3 to 7membered heterocycle optionally substituted with one or more groupsselected from OR^(f) and R^(g), and (h) a 5 to 6 membered heteroaryloptionally substituted with one or more groups selected from OR^(f) andR^(g);

R³ is selected from (a) (CR^(h)R^(i))_(x)-phenyl, wherein the phenyl maybe optionally substituted with one or more R^(j) groups, (b)(CR^(h)R^(i))_(x)-(5 to 6 membered heteroaryl), wherein the heteroarylmay be optionally substituted with one or more R^(j) groups, (c)(CR^(h)R^(i))_(x)-(9 to 10 membered bicyclic heterocycle), wherein theheterocycle may be optionally substituted with one or more R^(j) groups,and (d) (CR^(h)R^(i))_(x)-(9 to 10 membered bicyclic heteroaryl),wherein the heteroaryl may be optionally substituted with one or moreR^(j) groups;

each R⁴, R⁵, R⁶ and R⁷ is independently selected from hydrogen, halogenand C₁-C₃ alkyl;

each R^(a), R^(b), R^(c), R^(d) and R^(e) are independently selectedfrom hydrogen and C₁-C₆ alkyl;

R^(f) is selected from hydrogen and C₁-C₆ alkyl optionally substitutedwith one or more groups selected from oxo, NH₂, NH(C₁-C₃ alkyl) andN(C₁-C₃ alkyl)₂;

each R^(g) is C₁-C₆ alkyl;

R^(h) and R^(j) are independently selected from hydrogen, OR^(k) andC₁-C₆ alkyl optionally substituted with OR^(m);

each R^(j) is independently selected from halogen, CN, cyclopropyl,C₁-C₆ alkyl optionally substituted with halogen, and C₁-C₆ alkoxyoptionally substituted with halogen;

R^(k) and R^(m) are independently selected from hydrogen and C₁-C₃alkyl; and

x is 0 or 1.

In another embodiment, compounds of Formula I or a stereoisomer,tautomer or pharmaceutically acceptable salt thereof are provided.

In certain embodiments, X₁ is selected from CH and N; and X₂ is selectedfrom CR⁵ and N; wherein only one of X₁ and X₂ may be N.

In certain embodiments, Y₁ is selected from CR⁶ and N; and Y₂ isselected from CR⁷ and N; wherein only one of Y₁ and Y₂ may be N.

In certain embodiments, compounds of the invention have thestereochemical orientation represented by Formula II:

or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof,wherein X₁, X₂, Y₁ Y₂, R¹, R², R³ and R⁴ are as defined herein.

In certain embodiments, compounds of the invention have thestereochemical orientation represented by Formula III:

or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof,wherein X₁, X₂, Y₁ Y₂, R¹, R², R³ and R⁴ are as defined herein.

In certain embodiments, compounds of the invention have thestereochemical orientation represented by Formula IV:

or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof,wherein X₁, X₂, Y₁ Y₂, R¹, R², R³ and R⁴ are as defined herein.

In certain embodiments, compounds of the invention have thestereochemical orientation represented by Formula V:

or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof,wherein X₁, X₂, Y₁ Y₂, R¹, R², R³ and R⁴ are as defined herein.

In certain embodiments, compounds of the invention have the Formula VI:

or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof,wherein R¹, R², R³, R⁴, R⁵, R⁶ and R⁷ are as defined herein.

In certain embodiments, compounds of the invention have the Formula VII:

or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof,wherein R¹, R², R³, R⁴, R⁵ and R⁷ are as defined herein.

In certain embodiments, compounds of the invention have the FormulaVIII:

or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof,wherein R¹, R², R³, R⁴, R⁵ and R⁶ are as defined herein.

In certain embodiments, compounds of the invention have the Formula IX:

or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof,wherein R¹, R², R³, R⁴, R⁶ and R⁷ are as defined herein.

In certain embodiments, compounds of the invention have the Formula X:

or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof,wherein R¹, R², R³, R⁴, R⁵, R⁶ and R⁷ are as defined herein.

In certain embodiments:

X₁ is selected from CH and N;

X₂ is selected from CR⁵ and N;

Y₁ is selected from CR⁶ and N;

Y₂ is selected from CR⁷ and N;

R¹ is selected from (a) C₁-C₆ alkyl optionally substituted with one ormore groups independently selected from halogen, OR^(a), NR^(b)R^(c),oxo, CN, C₃-C₆ cycloalkyl and a 3 to 7 membered heterocycle, (b) C₃-C₇cycloalkyl optionally substituted with one or more groups independentlyselected from halogen, OR^(a), CN and C₁-C₃ alkyl optionally substitutedwith one or more groups independently selected from halogen and OR^(d),(c) phenyl optionally substituted with one or more groups independentlyselected from halogen, OR^(a), CN, C₃-C₆ cycloalkyl and C₁-C₃ alkyloptionally substituted with one or more groups independently selectedfrom halogen and OR^(d), (d) a 3 to 7 membered saturated or partiallyunsaturated heterocycle optionally substituted with one or more groupsindependently selected from halogen, OR^(a), oxo, CN, C₃-C₆ cycloalkyland C₁-C₃ alkyl optionally substituted with one or more groupsindependently selected from halogen and OR^(d), (e) a 5 to 6 memberedheteroaryl optionally substituted with one or more groups independentlyselected from halogen, OR^(e), oxide, CN, C₃-C₆ cycloalkyl and C₁-C₃alkyl optionally substituted with one or more groups independentlyselected from halogen, oxo and OR^(d), and (f) a 7 to 10 memberedbicyclic heterocycle optionally substituted with one or more groupsindependently selected from halogen, OR^(a), oxo, CN, C₃-C₆ cycloalkyland C₁-C₃ alkyl optionally substituted with one or more groupsindependently selected from halogen and OR^(d);

R² is selected from (a) hydrogen, (b) C₁-C₆ alkyl optionally substitutedwith one or more groups selected from OR^(f), oxo, NH₂, NH(C₁-C₃ alkyl)and N(C₁-C₃ alkyl)₂, (c) C₁-C₆ alkenyl optionally substituted with oneor more OR^(f) groups, (d) C₁-C₆ alkynyl optionally substituted with oneor more OR^(f) groups, (e) C₃-C₆ cycloalkyl optionally substituted withone or more groups selected from OR^(f) and R^(g), (f) phenyl optionallysubstituted with one or more groups selected from OR^(f) and R^(g), (g)a 3 to 7 membered heterocycle optionally substituted with one or moregroups selected from OR^(f) and R^(g), and (h) a 5 to 6 memberedheteroaryl optionally substituted with one or more groups selected fromOR^(f) and R^(g);

R³ is selected from (a) (CR^(h)R^(i))_(x)-phenyl, wherein the phenyl maybe optionally substituted with one or more R^(j) groups, (b) a 5 to 6membered heteroaryl optionally substituted with one or more R^(j)groups, (c) a 9 to 10 membered bicyclic heterocycle optionallysubstituted with one or more R^(j) groups, and (d) a 9 to 10 memberedbicyclic heteroaryl optionally substituted with one or more R^(j)groups;

each R⁴, R⁵, R⁶ and R⁷ is independently selected from hydrogen, halogenand C₁-C₃ alkyl;

each R^(a), R^(b), R^(c), R^(d) and R^(e) are independently selectedfrom hydrogen and C₁-C₆ alkyl;

R^(f) is selected from hydrogen and C₁-C₆ alkyl optionally substitutedwith one or more groups selected from oxo, NH₂, NH(C₁-C₃ alkyl) andN(C₁-C₃ alkyl)₂;

each R^(g) is C₁-C₆ alkyl;

R^(h) and R^(i) are independently selected from hydrogen, OR^(k) andC₁-C₆ alkyl optionally substituted with OR^(m);

each R^(j) is independently selected from halogen, CN, cyclopropyl,C₁-C₆ alkyl optionally substituted with halogen, and C₁-C₆ alkoxyoptionally substituted with halogen;

R^(k) and R^(m) are independently selected from hydrogen and C₁-C₃alkyl; and

x is 0 or 1.

In certain embodiments:

X₁ is selected from CH and N;

X₂ is selected from CR⁵ and N;

Y₁ is selected from CR⁶ and N;

Y₂ is selected from CR⁷ and N;

R¹ is selected from (a) C₁-C₆ alkyl optionally substituted with one ormore groups independently selected from halogen, OR^(a), NR^(b)R^(c),oxo, CN, C₃-C₆ cycloalkyl and a 3 to 7 membered heterocycle, (b) C₃-C₇cycloalkyl optionally substituted with one or more groups independentlyselected from halogen, OR^(a), CN and C₁-C₃ alkyl optionally substitutedwith one or more groups independently selected from halogen and OR^(d),(c) phenyl optionally substituted with one or more groups independentlyselected from halogen, OR^(a), CN, C₃-C₆ cycloalkyl and C₁-C₃ alkyloptionally substituted with one or more groups independently selectedfrom halogen and OR^(d), (d) a 3 to 7 membered saturated or partiallyunsaturated heterocycle optionally substituted with one or more groupsindependently selected from halogen, OR^(a), oxo, CN, C₃-C₆ cycloalkyland C₁-C₃ alkyl optionally substituted with one or more groupsindependently selected from halogen and OR^(d), (e) a 5 to 6 memberedheteroaryl optionally substituted with one or more groups independentlyselected from halogen, OR^(e), oxide, CN, C₃-C₆ cycloalkyl and C₁-C₃alkyl optionally substituted with one or more groups independentlyselected from halogen, oxo and OR^(d), and (f) a 7 to 10 memberedbicyclic heterocycle optionally substituted with one or more groupsindependently selected from halogen, OR^(a), oxo, CN, C₃-C₆ cycloalkyland C₁-C₃ alkyl optionally substituted with one or more groupsindependently selected from halogen and OR^(d);

R² is selected from (a) hydrogen, (b) C₁-C₆ alkyl optionally substitutedwith one or more groups selected from OR^(f) and oxo, (c) C₁-C₆ alkenyloptionally substituted with one or more OR^(f) groups, (d) C₁-C₆ alkynyloptionally substituted with one or more OR^(f) groups, (e) C₃-C₆cycloalkyl optionally substituted with one or more groups selected fromOR^(f) and R^(g), (f) phenyl optionally substituted with one or moregroups selected from OR^(f) and R^(g), (g) a 3 to 7 membered heterocycleoptionally substituted with one or more groups selected from OR^(f) andR^(g), and (h) a 5 to 6 membered heteroaryl optionally substituted withone or more groups selected from OR^(f) and R^(g);

R³ is selected from (a) (CR^(h)R^(i))_(x)-phenyl, wherein the phenyl maybe optionally substituted with one or more R^(j) groups, (b) a 5 to 6membered heteroaryl optionally substituted with one or more R^(j)groups, (c) a 9 to 10 membered heterocycle optionally substituted withone or more R^(j) groups, and (d) a 9 to 10 membered heteroaryloptionally substituted with one or more R^(j) groups;

each R⁴, R⁵, R⁶ and R⁷ is independently selected from hydrogen, halogenand C₁-C₃ alkyl;

each R^(a), R^(b), R^(c), R^(d), R^(e) and R^(f) are independentlyselected from hydrogen and C₁-C₆ alkyl;

each R^(g) is C₁-C₆ alkyl;

R^(h) and R^(i) are independently selected from hydrogen, OR^(k) andC₁-C₆ alkyl optionally substituted with OR^(m);

each R^(j) is independently selected from halogen, CN, cyclopropyl,C₁-C₆ alkyl optionally substituted with halogen, and C₁-C₆ alkoxyoptionally substituted with halogen;

R^(k) and R^(m) are independently hydrogen or C₁-C₃ alkyl; and

x is 0 or 1.

In certain embodiments, R¹ is selected from (a) C₁-C₆ alkyl optionallysubstituted with one or more groups independently selected from halogen,OR^(a), NR^(b)R^(c), oxo, CN, C₃-C₆ cycloalkyl and a 3 to 7 memberedheterocycle, wherein the heterocycle contains one, two or threeheteroatoms selected from the group consisting of O, N, S, S(═O) andS(═O)₂, (b) C₃-C₇ cycloalkyl optionally substituted with one or moregroups independently selected from halogen, OR^(a), CN and C₁-C₃ alkyloptionally substituted with one or more groups independently selectedfrom halogen and OR^(d), (c) phenyl optionally substituted with one ormore groups independently selected from halogen, OR^(a), CN, C₃-C₆cycloalkyl and C₁-C₃ alkyl optionally substituted with one or moregroups independently selected from halogen and OR^(d), (d) a 3 to 7membered saturated or partially unsaturated heterocycle optionallysubstituted with one or more groups independently selected from halogen,OR^(a), oxo, CN, C₃-C₆ cycloalkyl and C₁-C₃ alkyl optionally substitutedwith one or more groups independently selected from halogen and OR^(d),wherein the heterocycle contains one, two or three heteroatoms selectedfrom the group consisting of O, N, S, S(═O) and S(═O)₂, (e) a 5 to 6membered heteroaryl optionally substituted with one or more groupsindependently selected from halogen, OR^(e), oxide, CN, C₃-C₆ cycloalkyland C₁-C₃ alkyl optionally substituted with one or more groupsindependently selected from halogen, oxo and OR^(d), wherein theheteroaryl contains one, two, three or four heteroatoms selected fromthe group consisting of O, N and S, and (f) a 7 to 10 membered bicyclicheterocycle optionally substituted with one or more groups independentlyselected from halogen, OR^(a), oxo, CN, C₃-C₆ cycloalkyl and C₁-C₃ alkyloptionally substituted with one or more groups independently selectedfrom halogen and OR^(d), wherein the heterocycle contains one, two orthree heteroatoms selected from the group consisting of O, N, S, S(═O)and S(═O)₂.

In certain embodiments, R¹ is selected from (a) C₁-C₆ alkyl optionallysubstituted with one to six groups independently selected from halogen,OR^(a), NR^(b)R^(c), C₃-C₆ cycloalkyl and a 3 to 7 membered heterocycle,wherein the heterocycle contains one, two or three heteroatoms selectedfrom the group consisting of O, N, S, S(═O) and S(═O)₂, (b) C₃-C₇cycloalkyl optionally substituted with one to four groups independentlyselected from halogen and OR^(a), (c) phenyl optionally substituted withone to four groups independently selected from halogen and C₁-C₃ alkyl,(d) a 3 to 7 membered saturated or partially unsaturated heterocycleoptionally substituted with one to four groups independently selectedfrom halogen, oxo, OR^(a) and C₁-C₃ alkyl optionally substituted withOR^(d), wherein the heterocycle contains one, two or three heteroatomsselected from the group consisting of O, N, S, S(═O) and S(═O)₂, (e) a 5to 6 membered heteroaryl optionally substituted with one to four groupsindependently selected from halogen, CN, OR^(e), C₃-C₆ cycloalkyl, oxideand C₁-C₃ alkyl optionally substituted with one to three groupsindependently selected from hydroxyl, methoxy, oxo and halogen, whereinthe heteroaryl contains one, two, three or four heteroatoms selectedfrom the group consisting of O, N and S, and (f) a 7 to 10 memberedbicyclic heterocycle optionally substituted with one or two groupsselected from C₁-C₃ alkyl and oxo, wherein the heterocycle contains one,two or three heteroatoms selected from the group consisting of O, N, S,S(═O) and S(═O)₂.

In certain embodiments, each R^(a) is independently selected fromhydrogen and C₁-C₆ alkyl. In certain embodiments, each R^(a) isindependently selected from hydrogen and C₁-C₃ alkyl. In certainembodiments, each R^(a) is independently selected from hydrogen andmethyl.

In certain embodiments, each R^(b) and R^(c) are independently selectedfrom hydrogen and C₁-C₆ alkyl. In certain embodiments, each R^(b) andR^(c) are independently selected from hydrogen and C₁-C₃ alkyl. Incertain embodiments, each R^(b) and R^(c) are independently selectedfrom hydrogen and methyl.

In certain embodiments, each R^(d) is independently selected fromhydrogen and C₁-C₆ alkyl. In certain embodiments, each R^(d) isindependently selected from hydrogen and C₁-C₃ alkyl. In certainembodiments, each R^(d) is selected from hydrogen and methyl.

In certain embodiments, each R^(e) is independently selected fromhydrogen and C₁-C₆ alkyl. In certain embodiments, each R^(e) isindependently selected from hydrogen and C₁-C₃ alkyl. In certainembodiments, each R^(e) is independently selected from methyl and ethyl.

In certain embodiments, R¹ is selected from 1-hydroxypropan-2-yl,isopropyl, 1-hydroxybutan-2-yl, 1-cyclopropylethyl,1-hydroxy-3-methoxypropan-2-yl, 1,3-difluoropropan-2-yl,1-cyclopropyl-2-hydroxyethyl, oxetan-3-ylmethyl, 4-methoxybutan-2-yl,4,4,4-trifluoro-1-hydroxybutan-2-yl, 1-aminopropan-2-yl,3-hydroxycyclopentyl, 3,3-difluorocyclobutyl, 3-hydroxycyclobutyl,2-chloro-4-fluorophenyl, 4-fluoro-2-methylphenyl, tetrahydropyran-4-yl,3-fluorotetrahydropyran-4-yl, tetrahydrodioxothiopyran-4-yl,1,1-dioxotetrahydrothiophen-3-yl, oxetan-3-yl, tetrahydrofuran-3-yl,2,2-dimethyltetrahydropyran-4-yl, 2-methyltetrahydropyran-4-yl,pyrrolidin-3-yl, azetidin-3-yl, piperdin-3-yl,2-(hydroxymethyl)tetrahydropyran-4-yl, 6-oxo-1,6-dihydropyridin-3-yl,1-methylpyrazol-4-yl, 2-methylpyrimidin-4-yl, 6-methylpyrimidin-4-yl,6-methoxypyrimidin-4-yl, 2-methylpyridin-4-yl, 1,3-dimethylpyrazol-4-yl,2-methoxypyridin-4-yl, 1-methylpyrazol-3-yl, 6-methoxypyridin-3-yl,2-ethylpyrimidin-4-yl, 6-methylpyridin-2-yl,2-cyclopropylpyrimidin-4-yl, 5-fluoro-6-methylpyridin-2-yl,5-cyclopropyl-1-methylpyrazol-4-yl, 5-bromo-2-methylpyridin-4-yl,1,5-dimethylpyrazol-4-yl, 1,3-dimethylpyrazol-5-yl,4-(2-hydroxypropan-2-yl)pyridin-2-yl, 1-ethyl-3-methylpyrazol-4-yl,5-ethoxy-2-methylpyridin-4-yl, 1-isopropylpyrazol-4-yl,4-methylimidazol-5-yl, 1-methylimidazol-5-yl, 1-ethylpyrazol-4-yl,2-(2-hydroxypropan-2-yl)pyridin-4-yl, 1-methyl-4-cyanopyrazol-5-yl,3-methylpyridin-4-yl, 1-ethyl-3-methylpyrazol-5-yl,1-methylpyrazol-5-yl, 1,4-dimethylpyrazol-5-yl, 1-ethylpyrazol-5-yl,3-isopropyl-1-methylpyrazol-5-yl, 3-methylpyrazol-4-yl,3-ethyl-1-methylpyrazol-4-yl, 1,3,5-trimethylpyrazol-4-yl,3,5-dimethylpyrazol-4-yl, 2-cyclopropyl-5-methoxypyridin-4-yl,5-ethyl-1-methylpyrazol-4-yl, 4-(2-methoxypyridine 1-oxide),5-methoxy-2-methylpyridin-4-yl, 5-methyl-1,3,4-oxadizol-2-yl,3-ethyl-1-methylpyrazol-5-yl, 1-(2-hydroxyethyl)-3-methylpyrazol-4-yl,1-(2-hydroxyethyl)-5-methylpyrazol-4-yl,1-methyl-3-(trifluoromethyl)pyrazol-4-yl,1-methyl-3-(trifluoromethyl)pyrazol-5-yl, 1-methyl-1,2,3-triazol-5-yl,2-methylpyridin-4-yl, 1-(2-hydroxyethyl)pyrazol-5-yl, methyl4-picolinate, 4-picolinic acid, 1-cyclopropyl-5-methylpyrazol-4-yl,1-cyclopropyl-3-methylpyrazol-4-yl, 2,3-dimethylpyridin-4-yl,2,5-dimethylpyridin-4-yl, 1,3,4-oxadizol-2-yl, 3-methylpyridazin-4-yl,pyridazin-4-yl, tetrazol-5-yl, 1-methyltetrazol-5-yl,2-methyl-2,4,5,6-tetrahydrocyclopentapyrazol-3-yl,3-oxo-2-oxabicyclo[2.2.1]heptan-5-yl and 2-oxabicyclo[2.2.1]heptan-5-yl.

In certain embodiments, R¹ is selected from 1-hydroxypropan-2-yl,isopropyl, 1-hydroxybutan-2-yl, 1-cyclopropylethyl,1-hydroxy-3-methoxypropan-2-yl, 1,3-difluoropropan-2-yl,1-cyclopropyl-2-hydroxyethyl, oxetan-3-ylmethyl, 4-methoxybutan-2-yl,4,4,4-trifluoro-1-hydroxybutan-2-yl, 1-aminopropan-2-yl,3-hydroxycyclopentyl, 3,3-difluorocyclobutyl, 3-hydroxycyclobutyl,2-chloro-4-fluorophenyl, 4-fluoro-2-methylphenyl, tetrahydropyran-4-yl,3-fluorotetrahydropyran-4-yl, tetrahydrodioxothiopyran-4-yl,1,1-dioxotetrahydrothiophen-3-yl, oxetan-3-yl, tetrahydrofuran-3-yl,2,2-dimethyltetrahydropyran-4-yl, 2-methyltetrahydropyran-4-yl,pyrrolidin-3-yl, azetidin-3-yl, piperdin-3-yl,2-(hydroxymethyl)tetrahydropyran-4-yl, 6-oxo-1,6-dihydropyridin-3-yl,1-methylpyrazol-4-yl, 2-methylpyrimidin-4-yl, 6-methylpyrimidin-4-yl,6-methoxypyrimidin-4-yl, 2-methylpyridin-4-yl, 1,3-dimethylpyrazol-4-yl,2-methoxypyridin-4-yl, 1-methylpyrazol-3-yl, 6-methoxypyridin-3-yl,2-ethylpyrimidin-4-yl, 6-methylpyridin-2-yl,2-cyclopropylpyrimidin-4-yl, 5-fluoro-6-methylpyridin-2-yl,5-cyclopropyl-1-methylpyrazol-4-yl, 5-bromo-2-methylpyridin-4-yl,1,5-dimethylpyrazol-4-yl, 1,3-dimethylpyrazol-5-yl,4-(2-hydroxypropan-2-yl)pyridin-2-yl, 1-ethyl-3-methylpyrazol-4-yl,5-ethoxy-2-methylpyridin-4-yl, 1-isopropylpyrazol-4-yl,4-methylimidazol-5-yl, 1-methylimidazol-5-yl, 1-ethylpyrazol-4-yl,2-(2-hydroxypropan-2-yl)pyridin-4-yl, 1-methyl-4-cyanopyrazol-5-yl,3-methylpyridin-4-yl, 1-ethyl-3-methylpyrazol-5-yl,1-methylpyrazol-5-yl, 1,4-dimethylpyrazol-5-yl, 1-ethylpyrazol-5-yl,3-isopropyl-1-methylpyrazol-5-yl, 3-methylpyrazol-4-yl,3-ethyl-1-methylpyrazol-4-yl, 1,3,5-trimethylpyrazol-4-yl,3,5-dimethylpyrazol-4-yl, 2-cyclopropyl-5-methoxypyridin-4-yl,5-ethyl-1-methylpyrazol-4-yl, 4-(2-methoxypyridine 1-oxide),5-methoxy-2-methylpyridin-4-yl, 5-methyl-1,3,4-oxadizol-2-yl,3-ethyl-1-methylpyrazol-5-yl, 1-(2-hydroxyethyl)-3-methylpyrazol-4-yl,1-(2-hydroxyethyl)-5-methylpyrazol-4-yl,1-methyl-3-(trifluoromethyl)pyrazol-4-yl,1-methyl-3-(trifluoromethyl)pyrazol-5-yl, 1-methyl-1,2,3-triazol-5-yl,2-methylpyridin-4-yl, 1-(2-hydroxyethyl)pyrazol-5-yl, methyl4-picolinate, 4-picolinic acid, 1-cyclopropyl-5-methylpyrazol-4-yl,1-cyclopropyl-3-methylpyrazol-4-yl, 2,3-dimethylpyridin-4-yl,2,5-dimethylpyridin-4-yl, 1,3,4-oxadizol-2-yl, 3-methylpyridazin-4-yl,pyridazin-4-yl, 2-methyl-2,4,5,6-tetrahydrocyclopentapyrazol-3-yl,3-oxo-2-oxabicyclo[2.2.1]heptan-5-yl and 2-oxabicyclo[2.2.1]heptan-5-yl.

In certain embodiments, R¹ is selected from (a) C₁-C₆ alkyl optionallysubstituted with one or more groups independently selected from halogen,OR^(a), NR^(b)R^(c), oxo, CN, C₃-C₆ cycloalkyl and a 3 to 7 memberedheterocycle, wherein the heterocycle contains one, two or threeheteroatoms selected from the group consisting of O, N, S, S(═O) andS(═O)₂, (b) C₃-C₇ cycloalkyl optionally substituted with one or moregroups independently selected from halogen, OR^(a), CN and C₁-C₃ alkyloptionally substituted with one or more groups independently selectedfrom halogen and OR^(d), (c) phenyl optionally substituted with one ormore groups independently selected from halogen, OR^(a), CN, C₃-C₆cycloalkyl and C₁-C₃ alkyl optionally substituted with one or moregroups independently selected from halogen and OR^(d), (d) a 3 to 7membered saturated or partially unsaturated heterocycle optionallysubstituted with one or more groups independently selected from halogen,OR^(a), oxo, CN, C₃-C₆ cycloalkyl and C₁-C₃ alkyl optionally substitutedwith one or more groups independently selected from halogen and OR^(d),wherein the heterocycle contains one, two or three heteroatoms selectedfrom the group consisting of O, N, S, S(═O) and S(═O)₂, (e) a 5 to 6membered heteroaryl optionally substituted with one or more groupsindependently selected from halogen, OR^(e), CN, C₃-C₆ cycloalkyl andC₁-C₃ alkyl optionally substituted with one or more groups independentlyselected from halogen, oxo and OR^(d), wherein the heteroaryl containsone, two, three or four heteroatoms selected from the group consistingof O, N and S and (f) a 7 to 10 membered bicyclic heterocycle optionallysubstituted with one or more groups independently selected from halogen,OR^(a), oxo, CN, C₃-C₆ cycloalkyl and C₁-C₃ alkyl optionally substitutedwith one or more groups independently selected from halogen and OR^(d),wherein the heterocycle contains one, two or three heteroatoms selectedfrom the group consisting of O, N, S, S(═O) and S(═O)₂.

In certain embodiments, R¹ is selected from (a) C₁-C₆ alkyl optionallysubstituted with one to six groups independently selected from halogen,OR^(a), NR^(b)R^(c), C₃-C₆ cycloalkyl and a 3 to 7 membered heterocycle,wherein the heterocycle contains one, two or three heteroatoms selectedfrom the group consisting of O, N, S, S(═O) and S(═O)₂, (b) C₃-C₇cycloalkyl optionally substituted with one to four groups independentlyselected from halogen and OR^(a), (c) phenyl optionally substituted withone to four groups independently selected from halogen and C₁-C₃ alkyl,(d) a 3 to 7 membered saturated or partially unsaturated heterocycleoptionally substituted with one to four groups independently selectedfrom halogen, oxo, OR^(a), and C₁-C₃ alkyl optionally substituted withOR^(d), wherein the heterocycle contains one, two or three heteroatomsselected from the group consisting of O, N, S, S(═O) and S(═O)₂, (e) a 5to 6 membered heteroaryl optionally substituted with one to three groupsindependently selected from halogen, CN, OR^(e), cyclopropyl, and C₁-C₃alkyl optionally substituted with one to three groups independentlyselected from hydroxyl, methoxy, oxo and halogen, wherein the heteroarylcontains one, two, three or four heteroatoms selected from the groupconsisting of O, N and S, and (f) a 7 to 10 membered bicyclicheterocycle optionally substituted with one or two groups selected fromC₁-C₃ alkyl and oxo.

In certain embodiments, R¹ is selected from 1-hydroxypropan-2-yl,isopropyl, 1-hydroxybutan-2-yl, 1-cyclopropylethyl,1-hydroxy-3-methoxypropan-2-yl, 1,3-difluoropropan-2-yl,1-cyclopropyl-2-hydroxyethyl, oxetan-3-ylmethyl, 4-methoxybutan-2-yl,4,4,4-trifluoro-1-hydroxybutan-2-yl, 1-aminopropan-2-yl,3-hydroxycyclopentyl, 3,3-difluorocyclobutyl, 3-hydroxycyclobutyl,2-chloro-4-fluorophenyl, 4-fluoro-2-methylphenyl, tetrahydropyran-4-yl,3-fluorotetrahydropyran-4-yl, tetrahydrodioxothiopyran-4-yl,1,1-dioxotetrahydrothiophen-3-yl, oxetan-3-yl, tetrahydrofuran-3-yl,2,2-dimethyltetrahydropyran-4-yl, 2-methyltetrahydropyran-4-yl,pyrrolidin-3-yl, azetidin-3-yl, piperdin-3-yl,2-(hydroxymethyl)tetrahydropyran-4-yl, 6-oxo-1,6-dihydropyridin-3-yl,1-methylpyrazol-4-yl, 2-methylpyrimidin-4-yl, 6-methylpyrimidin-4-yl,6-methoxypyrimidin-4-yl, 2-methylpyridin-4-yl, 1,3-dimethylpyrazol-4-yl,2-methoxypyridin-4-yl, 1-methylpyrazol-3-yl, 6-methoxypyridin-3-yl,2-ethylpyrimidin-4-yl, 6-methylpyridin-2-yl,2-cyclopropylpyrimidin-4-yl, 5-fluoro-6-methylpyridin-2-yl,5-cyclopropyl-1-methylpyrazol-4-yl, 5-bromo-2-methylpyridin-4-yl,1,5-dimethylpyrazol-4-yl, 1,3-dimethylpyrazol-5-yl,4-(2-hydroxypropan-2-yl)pyridin-2-yl, 1-ethyl-3-methylpyrazol-4-yl,5-ethoxy-2-methylpyridin-4-yl, 1-isopropylpyrazol-4-yl,4-methylimidazol-5-yl, 1-methylimidazol-5-yl, 1-ethylpyrazol-4-yl,2-(2-hydroxypropan-2-yl)pyridin-4-yl, 1-methyl-4-cyanopyrazol-5-yl,3-methylpyridin-4-yl, 1-ethyl-3-methylpyrazol-5-yl,1-methylpyrazol-5-yl, 1,4-dimethylpyrazol-5-yl, 1-ethylpyrazol-5-yl,3-isopropyl-1-methylpyrazol-5-yl, 3-methylpyrazol-4-yl,3-ethyl-1-methylpyrazol-4-yl, 1,3,5-trimethylpyrazol-4-yl,3,5-dimethylpyrazol-4-yl, 2-cyclopropyl-5-methoxypyridin-4-yl,5-ethyl-1-methylpyrazol-4-yl, 5-methoxy-2-methylpyridin-4-yl,5-methyl-1,3,4-oxadizol-2-yl, 3-ethyl-1-methylpyrazol-5-yl,1-(2-hydroxyethyl)-3-methylpyrazol-4-yl,1-(2-hydroxyethyl)-5-methylpyrazol-4-yl,1-methyl-3-(trifluoromethyl)pyrazol-4-yl,1-methyl-3-(trifluoromethyl)pyrazol-5-yl and1-methyl-1,2,3-triazol-5-yl, 2-methylpyridin-4-yl,1-(2-hydroxyethyl)pyrazol-5-yl, methyl 4-picolinate, 4-picolinic acid,1-cyclopropyl-5-methylpyrazol-4-yl, 1-cyclopropyl-3-methylpyrazol-4-yl,2,3-dimethylpyridin-4-yl, 2,5-dimethylpyridin-4-yl, 1,3,4-oxadizol-2-yl,3-methylpyridazin-4-yl, pyridazin-4-yl, tetrazol-5-yl,1-methyltetrazol-5-yl,2-methyl-2,4,5,6-tetrahydrocyclopentapyrazol-3-yl,3-oxo-2-oxabicyclo[2.2.1]heptan-5-yl and 2-oxabicyclo[2.2.1]heptan-5-yl.

In certain embodiments, R¹ is selected from 1-hydroxypropan-2-yl,isopropyl, 1-hydroxybutan-2-yl, 1-cyclopropylethyl,1-hydroxy-3-methoxypropan-2-yl, 1,3-difluoropropan-2-yl,1-cyclopropyl-2-hydroxyethyl, oxetan-3-ylmethyl, 4-methoxybutan-2-yl,4,4,4-trifluoro-1-hydroxybutan-2-yl, 1-aminopropan-2-yl,3-hydroxycyclopentyl, 3,3-difluorocyclobutyl, 3-hydroxycyclobutyl,2-chloro-4-fluorophenyl, 4-fluoro-2-methylphenyl, tetrahydropyran-4-yl,3-fluorotetrahydropyran-4-yl, tetrahydrodioxothiopyran-4-yl,1,1-dioxotetrahydrothiophen-3-yl, oxetan-3-yl, tetrahydrofuran-3-yl,2,2-dimethyltetrahydropyran-4-yl, 2-methyltetrahydropyran-4-yl,pyrrolidin-3-yl, azetidin-3-yl, piperdin-3-yl,2-(hydroxymethyl)tetrahydropyran-4-yl, 6-oxo-1,6-dihydropyridin-3-yl,1-methylpyrazol-4-yl, 2-methylpyrimidin-4-yl, 6-methylpyrimidin-4-yl,6-methoxypyrimidin-4-yl, 2-methylpyridin-4-yl, 1,3-dimethylpyrazol-4-yl,2-methoxypyridin-4-yl, 1-methylpyrazol-3-yl, 6-methoxypyridin-3-yl,2-ethylpyrimidin-4-yl, 6-methylpyridin-2-yl,2-cyclopropylpyrimidin-4-yl, 5-fluoro-6-methylpyridin-2-yl,5-cyclopropyl-1-methylpyrazol-4-yl, 5-bromo-2-methylpyridin-4-yl,1,5-dimethylpyrazol-4-yl, 1,3-dimethylpyrazol-5-yl,4-(2-hydroxypropan-2-yl)pyridin-2-yl, 1-ethyl-3-methylpyrazol-4-yl,5-ethoxy-2-methylpyridin-4-yl, 1-isopropylpyrazol-4-yl,4-methylimidazol-5-yl, 1-methylimidazol-5-yl, 1-ethylpyrazol-4-yl,2-(2-hydroxypropan-2-yl)pyridin-4-yl, 1-methyl-4-cyanopyrazol-5-yl,3-methylpyridin-4-yl, 1-ethyl-3-methylpyrazol-5-yl,1-methylpyrazol-5-yl, 1,4-dimethylpyrazol-5-yl, 1-ethylpyrazol-5-yl,3-isopropyl-1-methylpyrazol-5-yl, 3-methylpyrazol-4-yl,3-ethyl-1-methylpyrazol-4-yl, 1,3,5-trimethylpyrazol-4-yl,3,5-dimethylpyrazol-4-yl, 2-cyclopropyl-5-methoxypyridin-4-yl,5-ethyl-1-methylpyrazol-4-yl, 5-methoxy-2-methylpyridin-4-yl,5-methyl-1,3,4-oxadizol-2-yl, 3-ethyl-1-methylpyrazol-5-yl,1-(2-hydroxyethyl)-3-methylpyrazol-4-yl,1-(2-hydroxyethyl)-5-methylpyrazol-4-yl,1-methyl-3-(trifluoromethyl)pyrazol-4-yl,1-methyl-3-(trifluoromethyl)pyrazol-5-yl and1-methyl-1,2,3-triazol-5-yl, 2-methylpyridin-4-yl,1-(2-hydroxyethyl)pyrazol-5-yl, methyl 4-picolinate, 4-picolinic acid,1-cyclopropyl-5-methylpyrazol-4-yl, 1-cyclopropyl-3-methylpyrazol-4-yl,2,3-dimethylpyridin-4-yl, 2,5-dimethylpyridin-4-yl, 1,3,4-oxadizol-2-yl,3-methylpyridazin-4-yl, pyridazin-4-yl,2-methyl-2,4,5,6-tetrahydrocyclopentapyrazol-3-yl,3-oxo-2-oxabicyclo[2.2.1]heptan-5-yl and 2-oxabicyclo[2.2.1]heptan-5-yl.

In certain embodiments, R¹ is selected from tetrahydropyran-4-yl,3-fluorotetrahydropyran-4-yl, 2-(hydroxymethyl)tetrahydropyran-4-yl,1,3-dimethylpyrazol-4-yl and 1-methylpyrazol-5-yl.

In certain embodiments, R¹ is C₁-C₆ alkyl optionally substituted withone to six groups independently selected from halogen, OR^(a),NR^(b)R^(c), C₃-C₆ cycloalkyl and a 3 to 7 membered heterocycle, whereinthe heterocycle contains one, two or three heteroatoms selected from thegroup consisting of O, N, S, S(═O) and S(═O)₂. In certain embodiments,R¹ is C₁-C₆ alkyl optionally substituted with one to four groupsindependently selected from halogen, OR^(a), NR^(b)R^(c), C₃-C₆cycloalkyl and a 3 to 7 membered heterocycle, wherein the heterocyclecontains one O heteroatom. In certain embodiments, R¹ is C₁-C₆ alkyloptionally substituted with one to four groups independently selectedfrom halogen, OR^(a), NR^(b)R^(c), cyclopropyl and oxetanyl. In certainembodiments, R¹ is selected from 1-hydroxypropan-2-yl, isopropyl,1-hydroxybutan-2-yl, 1-cyclopropylethyl, 1-hydroxy-3-methoxypropan-2-yl,1,3-difluoropropan-2-yl, 1-cyclopropyl-2-hydroxyethyl,oxetan-3-ylmethyl, 4-methoxybutan-2-yl,4,4,4-trifluoro-1-hydroxybutan-2-yl and 1-aminopropan-2-yl.

In certain embodiments, R¹ is C₃-C₇ cycloalkyl optionally substitutedwith one or two groups independently selected from halogen, C₁-C₃ alkyland OR^(a). In certain embodiments, R¹ is C₃-C₇ cycloalkyl optionallysubstituted with one or two groups independently selected from halogenand OR^(a). In certain embodiments, R¹ is selected from3-hydroxycyclopentyl, 3,3-difluorocyclobutyl and 3-hydroxycyclobutyl.

In certain embodiments, R¹ is phenyl optionally substituted with one ortwo groups independently selected from halogen, C₁-C₃ alkyl and OR^(a).In certain embodiments, R¹ is phenyl optionally substituted with one ortwo groups independently selected from halogen and C₁-C₃ alkyl. Incertain embodiments, R¹ is selected from 2-chloro-4-fluorophenyl and4-fluoro-2-methylphenyl.

In certain embodiments, R¹ is a 3 to 7 membered saturated or partiallyunsaturated heterocycle optionally substituted with one or two groupsindependently selected from halogen, oxo, OR^(a), and C₁-C₃ alkyloptionally substituted with OR^(d), wherein the heterocycle containsone, two or three heteroatoms selected from the group consisting of O,N, S, S(═O) and S(═O)₂. In certain embodiments, R¹ is a 3 to 7 memberedsaturated or partially unsaturated heterocycle optionally substitutedwith one or two groups independently selected from halogen, oxo andC₁-C₃ alkyl optionally substituted with OR^(d), wherein the heterocyclecontains one, two or three heteroatoms selected from the groupconsisting of O, N, S, S(═O) and S(═O)₂. In certain embodiments, R¹ is a3 to 7 membered saturated or partially unsaturated heterocycleoptionally substituted with one or two groups independently selectedfrom halogen, oxo, OR^(a), and C₁-C₃ alkyl optionally substituted withOR^(d), wherein the heterocycle contains one heteroatom selected fromthe group consisting of O, N and S(═O)₂. In certain embodiments, R¹ is a3 to 7 membered saturated or partially unsaturated heterocycleoptionally substituted with one or two groups independently selectedfrom halogen, oxo and C₁-C₃ alkyl optionally substituted with OR^(d),wherein the heterocycle contains one heteroatom selected from the groupconsisting of O, N and S(═O)₂. In certain embodiments, R¹ is selectedfrom tetrahydropyran-4-yl, 3-fluorotetrahydropyran-4-yl,tetrahydrodioxothiopyran-4-yl, 1,1-dioxotetrahydrothiophen-3-yl,oxetan-3-yl, tetrahydrofuran-3-yl, 2,2-dimethyltetrahydropyran-4-yl,2-methyltetrahydropyran-4-yl, pyrrolidin-3-yl, azetidin-3-yl,piperdin-3-yl, 2-(hydroxymethyl)tetrahydropyran-4-yl and6-oxo-1,6-dihydropyridin-3-yl.

In certain embodiments, R¹ is a 3 to 7 membered saturated heterocycleoptionally substituted with one or two groups independently selectedfrom halogen, oxo, OR^(a), and C₁-C₃ alkyl optionally substituted withOR^(d), wherein the heterocycle contains one, two or three heteroatomsselected from the group consisting of O, N, S, S(═O) and S(═O)₂. Incertain embodiments, R¹ is a 3 to 7 membered saturated heterocycleoptionally substituted with one or two groups independently selectedfrom halogen and C₁-C₃ alkyl optionally substituted with OH, wherein theheterocycle contains one, two or three heteroatoms selected from thegroup consisting of O, N, S, S(═O) and S(═O)₂. In certain embodiments,R¹ is a 3 to 7 membered saturated heterocycle optionally substitutedwith one or two groups independently selected from halogen, oxo, OR^(a),and C₁-C₃ alkyl optionally substituted with OR^(d), wherein theheterocycle contains one heteroatom selected from the group consistingof O, N and S(═O)₂. In certain embodiments, R¹ is a 3 to 7 memberedsaturated heterocycle optionally substituted with one or two groupsindependently selected from halogen and C₁-C₃ alkyl optionallysubstituted with OH, wherein the heterocycle contains one heteroatomselected from the group consisting of O, N and S(═O)₂. In certainembodiments, R¹ is selected from tetrahydropyran-4-yl,3-fluorotetrahydropyran-4-yl, tetrahydrodioxothiopyran-4-yl,1,1-dioxotetrahydrothiophen-3-yl, oxetan-3-yl, tetrahydrofuran-3-yl,2,2-dimethyltetrahydropyran-4-yl, 2-methyltetrahydropyran-4-yl,pyrrolidin-3-yl, azetidin-3-yl, piperdin-3-yl and2-(hydroxymethyl)tetrahydropyran-4-yl.

In certain embodiments, R¹ is a 3 to 7 membered partially unsaturatedheterocycle optionally substituted with one or two groups independentlyselected from halogen, oxo, OR^(a), and C₁-C₃ alkyl optionallysubstituted with OR^(d), wherein the heterocycle contains one, two orthree heteroatoms selected from the group consisting of O, N, S, S(═O)and S(═O)₂. In certain embodiments, R¹ is a 3 to 7 membered partiallyunsaturated heterocycle optionally substituted with one oxo group,wherein the heterocycle contains one, two or three heteroatoms selectedfrom the group consisting of O, N, S, S(═O) and S(═O)₂. In certainembodiments, R¹ is a 3 to 7 membered partially unsaturated heterocycleoptionally substituted with one or two groups independently selectedfrom halogen, oxo, OR^(a), and C₁-C₃ alkyl optionally substituted withOR^(d), wherein the heterocycle contains one N heteroatom. In certainembodiments, R¹ is a 3 to 7 membered partially unsaturated heterocycleoptionally substituted with one oxo group, wherein the heterocyclecontains one N heteroatom. In certain embodiments, R¹ is6-oxo-1,6-dihydropyridin-3-yl.

In certain embodiments, R¹ is a 5 to 6 membered heteroaryl optionallysubstituted with one to three groups independently selected fromhalogen, CN, OR^(e), cyclopropyl, oxide and C₁-C₃ alkyl optionallysubstituted with one to three groups independently selected fromhydroxyl, methoxy, oxo and halogen, wherein the heteroaryl contains one,two, three or four heteroatoms selected from the group consisting of O,N and S. In certain embodiments, R¹ is a 5 to 6 membered heteroaryloptionally substituted with one to three groups independently selectedfrom halogen, CN, OR^(e), cyclopropyl, oxide and C₁-C₃ alkyl optionallysubstituted with one to three groups independently selected fromhydroxyl, methoxy, oxo and halogen, wherein the heteroaryl contains one,two, three or four heteroatoms selected from the group consisting of Oand N. In certain embodiments, R¹ is a 5 to 6 membered heteroaryloptionally substituted with one to three groups independently selectedfrom halogen, CN, OR^(e), cyclopropyl, oxide and C₁-C₃ alkyl optionallysubstituted with one to three groups independently selected fromhydroxyl, methoxy, oxo and halogen, wherein the heteroaryl contains one,two or three heteroatoms selected from the group consisting of O and N.In certain embodiments, R¹ is a 5 to 6 membered heteroaryl optionallysubstituted with one to three groups independently selected fromhalogen, CN, OR^(e), cyclopropyl and C₁-C₃ alkyl optionally substitutedwith one to three groups independently selected from hydroxyl, methoxy,oxo and halogen, wherein the heteroaryl contains one, two, three or fourheteroatoms selected from the group consisting of O and N. In certainembodiments, R¹ is a 5 to 6 membered heteroaryl optionally substitutedwith one to three groups independently selected from halogen, CN,OR^(e), cyclopropyl and C₁-C₃ alkyl optionally substituted with one tothree groups independently selected from hydroxyl, methoxy, oxo andhalogen, wherein the heteroaryl contains one, two or three heteroatomsselected from the group consisting of O and N. In certain embodiments,R¹ is a 5 to 6 membered heteroaryl optionally substituted with one ortwo groups independently selected from methyl, ethyl and CF₃, whereinthe heteroaryl contains one or two N heteroatoms. In certainembodiments, R¹ is selected from 1-methylpyrazol-4-yl,2-methylpyrimidin-4-yl, 6-methylpyrimidin-4-yl, 6-methoxypyrimidin-4-yl,2-methylpyridin-4-yl, 1,3-dimethylpyrazol-4-yl, 2-methoxypyridin-4-yl,1-methylpyrazol-3-yl, 6-methoxypyridin-3-yl, 2-ethylpyrimidin-4-yl,6-methylpyridin-2-yl, 2-cyclopropylpyrimidin-4-yl,5-fluoro-6-methylpyridin-2-yl, 5-cyclopropyl-1-methylpyrazol-4-yl,5-bromo-2-methylpyridin-4-yl, 1,5-dimethylpyrazol-4-yl,1,3-dimethylpyrazol-5-yl, 4-(2-hydroxypropan-2-yl)pyridin-2-yl,1-ethyl-3-methylpyrazol-4-yl, 5-ethoxy-2-methylpyridin-4-yl,1-isopropylpyrazol-4-yl, 4-methylimidazol-5-yl, 1-methylimidazol-5-yl,1-ethylpyrazol-4-yl, 2-(2-hydroxypropan-2-yl)pyridin-4-yl,1-methyl-4-cyanopyrazol-5-yl, 3-methylpyridin-4-yl,1-ethyl-3-methylpyrazol-5-yl, 1-methylpyrazol-5-yl,1,4-dimethylpyrazol-5-yl, 1-ethylpyrazol-5-yl,3-isopropyl-1-methylpyrazol-5-yl, 3-methylpyrazol-4-yl,3-ethyl-1-methylpyrazol-4-yl, 1,3,5-trimethylpyrazol-4-yl,3,5-dimethylpyrazol-4-yl, 2-cyclopropyl-5-methoxypyridin-4-yl,5-ethyl-1-methylpyrazol-4-yl, 4-(2-methoxypyridine 1-oxide),5-methoxy-2-methylpyridin-4-yl, 5-methyl-1,3,4-oxadizol-2-yl,3-ethyl-1-methylpyrazol-5-yl, 1-(2-hydroxyethyl)-3-methylpyrazol-4-yl,1-(2-hydroxyethyl)-5-methylpyrazol-4-yl,1-methyl-3-(trifluoromethyl)pyrazol-4-yl,1-methyl-3-(trifluoromethyl)pyrazol-5-yl, 1-methyl-1,2,3-triazol-5-yl,2-methylpyridin-4-yl, 1-(2-hydroxyethyl)pyrazol-5-yl, methyl4-picolinate, 4-picolinic acid, 1-cyclopropyl-5-methylpyrazol-4-yl,1-cyclopropyl-3-methylpyrazol-4-yl, 2,3-dimethylpyridin-4-yl,2,5-dimethylpyridin-4-yl, 1,3,4-oxadizol-2-yl, 3-methylpyridazin-4-yl,pyridazin-4-yl, tetrazol-5-yl and 1-methyltetrazol-5-yl. In certainembodiments, R¹ is selected from 1-methylpyrazol-4-yl,2-methylpyrimidin-4-yl, 6-methylpyrimidin-4-yl, 6-methoxypyrimidin-4-yl,2-methylpyridin-4-yl, 1,3-dimethylpyrazol-4-yl, 2-methoxypyridin-4-yl,1-methylpyrazol-3-yl, 6-methoxypyridin-3-yl, 2-ethylpyrimidin-4-yl,6-methylpyridin-2-yl, 2-cyclopropylpyrimidin-4-yl,5-fluoro-6-methylpyridin-2-yl, 5-cyclopropyl-1-methylpyrazol-4-yl,5-bromo-2-methylpyridin-4-yl, 1,5-dimethylpyrazol-4-yl,1,3-dimethylpyrazol-5-yl, 4-(2-hydroxypropan-2-yl)pyridin-2-yl,1-ethyl-3-methylpyrazol-4-yl, 5-ethoxy-2-methylpyridin-4-yl,1-isopropylpyrazol-4-yl, 4-methylimidazol-5-yl, 1-methylimidazol-5-yl,1-ethylpyrazol-4-yl, 2-(2-hydroxypropan-2-yl)pyridin-4-yl,1-methyl-4-cyanopyrazol-5-yl, 3-methylpyridin-4-yl,1-ethyl-3-methylpyrazol-5-yl, 1-methylpyrazol-5-yl,1,4-dimethylpyrazol-5-yl, 1-ethylpyrazol-5-yl,3-isopropyl-1-methylpyrazol-5-yl, 3-methylpyrazol-4-yl,3-ethyl-1-methylpyrazol-4-yl, 1,3,5-trimethylpyrazol-4-yl,3,5-dimethylpyrazol-4-yl, 2-cyclopropyl-5-methoxypyridin-4-yl,5-ethyl-1-methylpyrazol-4-yl, 5-methoxy-2-methylpyridin-4-yl,5-methyl-1,3,4-oxadizol-2-yl, 3-ethyl-1-methylpyrazol-5-yl,1-(2-hydroxyethyl)-3-methylpyrazol-4-yl,1-(2-hydroxyethyl)-5-methylpyrazol-4-yl,1-methyl-3-(trifluoromethyl)pyrazol-4-yl,1-methyl-3-(trifluoromethyl)pyrazol-5-yl, 1-methyl-1,2,3-triazol-5-yl,2-methylpyridin-4-yl, 1-(2-hydroxyethyl)pyrazol-5-yl, methyl4-picolinate, 4-picolinic acid, 1-cyclopropyl-5-methylpyrazol-4-yl,1-cyclopropyl-3-methylpyrazol-4-yl, 2,3-dimethylpyridin-4-yl,2,5-dimethylpyridin-4-yl, 1,3,4-oxadizol-2-yl, 3-methylpyridazin-4-yl,pyridazin-4-yl, tetrazol-5-yl and 1-methyltetrazol-5-yl.

In certain embodiments, R¹ is selected from 1-methylpyrazol-4-yl,2-methylpyrimidin-4-yl, 6-methylpyrimidin-4-yl, 6-methoxypyrimidin-4-yl,2-methylpyridin-4-yl, 1,3-dimethylpyrazol-4-yl, 2-methoxypyridin-4-yl,1-methylpyrazol-3-yl, 6-methoxypyridin-3-yl, 2-ethylpyrimidin-4-yl,6-methylpyridin-2-yl, 2-cyclopropylpyrimidin-4-yl,5-fluoro-6-methylpyridin-2-yl, 5-cyclopropyl-1-methylpyrazol-4-yl,5-bromo-2-methylpyridin-4-yl, 1,5-dimethylpyrazol-4-yl,1,3-dimethylpyrazol-5-yl, 4-(2-hydroxypropan-2-yl)pyridin-2-yl,1-ethyl-3-methylpyrazol-4-yl, 5-ethoxy-2-methylpyridin-4-yl,1-isopropylpyrazol-4-yl, 4-methylimidazol-5-yl, 1-methylimidazol-5-yl,1-ethylpyrazol-4-yl, 2-(2-hydroxypropan-2-yl)pyridin-4-yl,1-methyl-4-cyanopyrazol-5-yl, 3-methylpyridin-4-yl,1-ethyl-3-methylpyrazol-5-yl, 1-methylpyrazol-5-yl,1,4-dimethylpyrazol-5-yl, 1-ethylpyrazol-5-yl,3-isopropyl-1-methylpyrazol-5-yl, 3-methylpyrazol-4-yl,3-ethyl-1-methylpyrazol-4-yl, 1,3,5-trimethylpyrazol-4-yl,3,5-dimethylpyrazol-4-yl, 2-cyclopropyl-5-methoxypyridin-4-yl,5-ethyl-1-methylpyrazol-4-yl, 4-(2-methoxypyridine-1-oxide),5-methoxy-2-methylpyridin-4-yl, 5-methyl-1,3,4-oxadizol-2-yl,3-ethyl-1-methylpyrazol-5-yl, 1-(2-hydroxyethyl)-3-methylpyrazol-4-yl,1-(2-hydroxyethyl)-5-methylpyrazol-4-yl,1-methyl-3-(trifluoromethyl)pyrazol-4-yl,1-methyl-3-(trifluoromethyl)pyrazol-5-yl, 1-methyl-1,2,3-triazol-5-yl,2-methylpyridin-4-yl, 1-(2-hydroxyethyl)pyrazol-5-yl, methyl4-picolinate, 4-picolinic acid, 1-cyclopropyl-5-methylpyrazol-4-yl,1-cyclopropyl-3-methylpyrazol-4-yl, 2,3-dimethylpyridin-4-yl,2,5-dimethylpyridin-4-yl, 1,3,4-oxadizol-2-yl, 3-methylpyridazin-4-yland pyridazin-4-yl. In certain embodiments, R¹ is selected from1-methylpyrazol-4-yl, 2-methylpyrimidin-4-yl, 6-methylpyrimidin-4-yl,6-methoxypyrimidin-4-yl, 2-methylpyridin-4-yl, 1,3-dimethylpyrazol-4-yl,2-methoxypyridin-4-yl, 1-methylpyrazol-3-yl, 6-methoxypyridin-3-yl,2-ethylpyrimidin-4-yl, 6-methylpyridin-2-yl,2-cyclopropylpyrimidin-4-yl, 5-fluoro-6-methylpyridin-2-yl,5-cyclopropyl-1-methylpyrazol-4-yl, 5-bromo-2-methylpyridin-4-yl,1,5-dimethylpyrazol-4-yl, 1,3-dimethylpyrazol-5-yl,4-(2-hydroxypropan-2-yl)pyridin-2-yl, 1-ethyl-3-methylpyrazol-4-yl,5-ethoxy-2-methylpyridin-4-yl, 1-isopropylpyrazol-4-yl,4-methylimidazol-5-yl, 1-methylimidazol-5-yl, 1-ethylpyrazol-4-yl,2-(2-hydroxypropan-2-yl)pyridin-4-yl, 1-methyl-4-cyanopyrazol-5-yl,3-methylpyridin-4-yl, 1-ethyl-3-methylpyrazol-5-yl,1-methylpyrazol-5-yl, 1,4-dimethylpyrazol-5-yl, 1-ethylpyrazol-5-yl,3-isopropyl-1-methylpyrazol-5-yl, 3-methylpyrazol-4-yl,3-ethyl-1-methylpyrazol-4-yl, 1,3,5-trimethylpyrazol-4-yl,3,5-dimethylpyrazol-4-yl, 2-cyclopropyl-5-methoxypyridin-4-yl,5-ethyl-1-methylpyrazol-4-yl, 5-methoxy-2-methylpyridin-4-yl,5-methyl-1,3,4-oxadizol-2-yl, 3-ethyl-1-methylpyrazol-5-yl,1-(2-hydroxyethyl)-3-methylpyrazol-4-yl,1-(2-hydroxyethyl)-5-methylpyrazol-4-yl,1-methyl-3-(trifluoromethyl)pyrazol-4-yl,1-methyl-3-(trifluoromethyl)pyrazol-5-yl, 1-methyl-1,2,3-triazol-5-yl,2-methylpyridin-4-yl, 1-(2-hydroxyethyl)pyrazol-5-yl, methyl4-picolinate, 4-picolinic acid, 1-cyclopropyl-5-methylpyrazol-4-yl,1-cyclopropyl-3-methylpyrazol-4-yl, 2,3-dimethylpyridin-4-yl,2,5-dimethylpyridin-4-yl, 1,3,4-oxadizol-2-yl, 3-methylpyridazin-4-yland pyridazin-4-yl.

In certain embodiments, R¹ is a 7 to 10 membered bicyclic heterocycleoptionally substituted with one or two groups selected from C₁-C₃ alkyland oxo, wherein the heterocycle contains one, two or three heteroatomsselected from the group consisting of O, N, S, S(═O) and S(═O)₂. Incertain embodiments, R¹ is a 7 to 10 membered bicyclic heterocycleoptionally substituted with one or two groups selected from C₁-C₃ alkyland oxo, wherein the heterocycle contains one, two or three heteroatomsselected from O and N. In certain embodiments, R¹ is a 7 to 10 memberedbicyclic heterocycle optionally substituted with one or two groupsselected from C₁-C₃ alkyl and oxo, wherein the heterocycle contains oneor two heteroatoms selected from O and N. In certain embodiments, R¹ isselected from 2-methyl-2,4,5,6-tetrahydrocyclopentapyrazol-3-yl,3-oxo-2-oxabicyclo[2.2.1]heptan-5-yl and 2-oxabicyclo[2.2.1]heptan-5-yl.

In certain embodiments, R² is selected from (a) hydrogen, (b) C₁-C₆alkyl optionally substituted with one or more groups selected fromOR^(f), oxo, NH₂, NH(C₁-C₃ alkyl) and N(C₁-C₃ alkyl)₂, (c) C₁-C₆ alkenyloptionally substituted with one or more groups selected from OR^(f),oxo, NH₂, NH(C₁-C₃ alkyl) and N(C₁-C₃ alkyl)₂, (d) C₁-C₆ alkynyloptionally substituted with one or more groups selected from OR^(f),oxo, NH₂, NH(C₁-C₃ alkyl) and N(C₁-C₃ alkyl)₂, (e) C₃-C₆ cycloalkyloptionally substituted with one or more groups selected from OR^(f) andR^(g), (f) phenyl optionally substituted with one or more groupsselected from OR^(f) and R^(g), (g) a 3 to 7 membered heterocycleoptionally substituted with one or more groups selected from OR^(f) andR^(g), wherein the heterocycle contains one, two or three heteroatomsselected from the group consisting of O, N, S, S(═O) and S(═O)₂, and (h)a 5 to 6 membered heteroaryl optionally substituted with one or moregroups selected from OR^(f) and R^(g), wherein the heteroaryl containsone, two, three or four heteroatoms selected from the group consistingof O, N and S. In certain embodiments, R² is selected from (a) hydrogen,(b) C₁-C₆ alkyl optionally substituted with one or more groups selectedfrom OR^(f), oxo, NH₂, NH(C₁-C₃ alkyl) and N(C₁-C₃ alkyl)₂, (c) C₁-C₆alkenyl optionally substituted with one or more OR^(f) groups, (d) C₁-C₆alkynyl optionally substituted with one or more OR^(f) groups, (e) C₃-C₆cycloalkyl optionally substituted with one or more groups selected fromOR^(f) and R^(g), (f) phenyl optionally substituted with one or moregroups selected from OR^(f) and R^(g), (g) a 3 to 7 membered heterocycleoptionally substituted with one or more groups selected from OR^(f) andR^(g), wherein the heterocycle contains one, two or three heteroatomsselected from the group consisting of O, N, S, S(═O) and S(═O)₂, and (h)a 5 to 6 membered heteroaryl optionally substituted with one or moregroups selected from OR^(f) and R^(g), wherein the heteroaryl containsone, two, three or four heteroatoms selected from the group consistingof O, N and S.

In certain embodiments, R² is selected from (a) hydrogen, (b) C₁-C₆alkyl optionally substituted with one or more groups selected fromOR^(f) and oxo, (c) C₁-C₆ alkenyl optionally substituted with one ormore OR^(f) groups, (d) C₁-C₆ alkynyl optionally substituted with one ormore OR^(f) groups, (e) C₃-C₆ cycloalkyl optionally substituted with oneor more groups selected from OR^(f) and R^(g), (f) phenyl optionallysubstituted with one or more groups selected from OR^(f) and R^(g), (g)a 3 to 7 membered heterocycle optionally substituted with one or moregroups selected from OR^(f) and R^(g), wherein the heterocycle containsone, two or three heteroatoms selected from the group consisting of O,N, S, S(═O) and S(═O)₂, and (h) a 5 to 6 membered heteroaryl optionallysubstituted with one or more groups selected from OR^(f) and R^(g),wherein the heteroaryl contains one, two, three or four heteroatomsselected from the group consisting of O, N and S.

In certain embodiments, R² is selected from (a) hydrogen, (b) C₁-C₆alkyl optionally substituted with one or more groups selected fromOR^(f), oxo, NH₂, NH(C₁-C₃ alkyl) and N(C₁-C₃ alkyl)₂, (c) C₁-C₆ alkenyloptionally substituted with one or more OR^(f) groups, (f) phenyloptionally substituted with one or more groups selected from OR^(f) andR^(g), (g) a 3 to 7 membered heterocycle optionally substituted with oneor more groups selected from OR^(f) and R^(g), wherein the heterocyclecontains one, two or three heteroatoms selected from the groupconsisting of O, N, S, S(═O) and S(═O)₂, and (h) a 5 to 6 memberedheteroaryl optionally substituted with one or more groups selected fromOR^(f) and R^(g), wherein the heteroaryl contains one, two, three orfour heteroatoms selected from the group consisting of O, N and S. Incertain embodiments, R² is selected from (a) hydrogen, (b) C₁-C₆ alkyloptionally substituted with one or more groups selected from OR^(f),oxo, and NH₂, (c) C₁-C₆ alkenyl optionally substituted with one or moreOR^(f) groups, (f) phenyl optionally substituted with one or more groupsselected from OR^(f) and R^(g), (g) a 3 to 7 membered heterocycleoptionally substituted with one or more groups selected from OR^(f) andR^(g), wherein the heterocycle contains one, two or three heteroatomsselected from the group consisting of O, N, S, S(═O) and S(═O)₂, and (h)a 5 to 6 membered heteroaryl optionally substituted with one or moregroups selected from OR^(f) and R^(g), wherein the heteroaryl containsone, two, three or four heteroatoms selected from the group consistingof O, N and S.

In certain embodiments, R² is selected from (a) hydrogen, (b) C₁-C₆alkyl optionally substituted with one or more groups selected fromOR^(f) and oxo, (c) C₁-C₆ alkenyl optionally substituted with one ormore groups selected from OR^(f), (f) phenyl optionally substituted withone or more groups selected from OR^(f) and R^(g), (g) a 3 to 7 memberedheterocycle optionally substituted with one or more groups selected fromOR^(f) and R^(g), wherein the heterocycle contains one, two or threeheteroatoms selected from the group consisting of O, N, S, S(═O) andS(═O)₂, and (h) a 5 to 6 membered heteroaryl optionally substituted withone or more groups selected from OR^(f) and R^(g), wherein theheteroaryl contains one, two, three or four heteroatoms selected fromthe group consisting of O, N and S.

In certain embodiments, R^(f) is selected from hydrogen and C₁-C₆ alkyloptionally substituted with one or more groups selected from oxo, NH₂,NH(C₁-C₃ alkyl) and N(C₁-C₃ alkyl)₂. In certain embodiments, R^(f) isselected from hydrogen and C₁-C₆ alkyl optionally substituted with oneor more groups selected from oxo and NH₂. In certain embodiments, R^(f)is hydrogen, methyl, C(═O)C(CH₃)₂NH₂ or C(═O)CH₃.

In certain embodiments, R^(f) is selected from hydrogen and C₁-C₆ alkyl.In certain embodiments, R^(f) is hydrogen or methyl.

In certain embodiments, R^(g) is methyl.

In certain embodiments, R² is selected from hydrogen, methyl, ethyl,CH₂OH, CH₂CH₂OH, CH₂CH(OH)CH₃, CH₂C(CH₃)₂OH, CH₂OCH₃, C(═O)OH,CH₂OC(═O)C(CH₃)₂NH₂, CH₂OC(═O)CH₃, CH₂NH₂, methylene, phenyl,pyrrolidin-2-yl, pyrrolidin-3-yl, oxazol-5-yl and 1-methyl-pyrazol-4-yl.In certain embodiments, R² is selected from methyl, ethyl, CH₂OH,CH₂CH₂OH, CH₂CH(OH)CH₃, CH₂C(CH₃)₂OH, CH₂OCH₃, CH₂OC(═O)C(CH₃)₂NH₂,CH₂OC(═O)CH₃, CH₂NH₂, pyrrolidin-2-yl, pyrrolidin-3-yl, oxazol-5-yl, and1-methyl-pyrazol-4-yl. In certain embodiments, R² is selected fromCH₂OH, CH₂CH₂OH, CH₂CH(OH)CH₃, CH₂C(CH₃)₂OH, CH₂OCH₃,CH₂OC(═O)C(CH₃)₂NH₂, CH₂OC(═O)CH₃, CH₂NH₂, pyrrolidin-2-yl,pyrrolidin-3-yl, oxazol-5-yl, and 1-methyl-pyrazol-4-yl. In certainembodiments, R² is selected from pyrrolidin-2-yl, pyrrolidin-3-yl,oxazol-5-yl and 1-methyl-pyrazol-4-yl. In certain embodiments, R² isselected from CH₂OH, CH₂CH₂OH, CH₂CH(OH)CH₃, CH₂C(CH₃)₂OH,CH₂OC(═O)C(CH₃)₂NH₂, CH₂OC(═O)CH₃, CH₂NH₂ and 1-methyl-pyrazol-4-yl.

In certain embodiments, R² is selected from hydrogen, methyl, ethyl,CH₂OH, CH₂CH₂OH, CH₂CH(OH)CH₃, CH₂C(CH₃)₂OH, CH₂OCH₃, C(═O)OH,methylene, phenyl, pyrrolidin-2-yl, pyrrolidin-3-yl, oxazol-5-yl and1-methyl-pyrazol-4-yl. In certain embodiments, R² is selected frommethyl, ethyl, CH₂OH, CH₂CH₂OH, CH₂CH(OH)CH₃, CH₂C(CH₃)₂OH, CH₂OCH₃,pyrrolidin-2-yl, pyrrolidin-3-yl, oxazol-5-yl, and1-methyl-pyrazol-4-yl. In certain embodiments, R² is selected fromCH₂OH, CH₂CH₂OH, CH₂CH(OH)CH₃, CH₂C(CH₃)₂OH, CH₂OCH₃, pyrrolidin-2-yl,pyrrolidin-3-yl, oxazol-5-yl, and 1-methyl-pyrazol-4-yl. In certainembodiments, R² is selected from pyrrolidin-2-yl, pyrrolidin-3-yl,oxazol-5-yl and 1-methyl-pyrazol-4-yl. In certain embodiments, R² isselected from CH₂OH, CH₂CH₂OH, CH₂CH(OH)CH₃, CH₂C(CH₃)₂OH and1-methyl-pyrazol-4-yl.

In certain embodiments, R² is selected from (a) hydrogen, (b) C₁-C₆alkyl optionally substituted with one or two groups selected fromOR^(f), oxo, and NH₂, (c) C₁-C₆ alkenyl, (f) phenyl, (g) a 3 to 7membered heterocycle, wherein the heterocycle contains one, two or threeheteroatoms selected from the group consisting of O, N, S, S(═O) andS(═O)₂, and (h) a 5 to 6 membered heteroaryl optionally substituted withone R^(g) group, wherein the heteroaryl contains one, two, three or fourheteroatoms selected from the group consisting of O, N and S.

In certain embodiments, R² is selected from (a) hydrogen, (b) C₁-C₆alkyl optionally substituted with one or two groups selected from OR^(f)and oxo, (c) C₁-C₆ alkenyl, (f) phenyl, (g) a 3 to 7 memberedheterocycle, wherein the heterocycle contains one, two or threeheteroatoms selected from the group consisting of O, N, S, S(═O) andS(═O)₂, and (h) a 5 to 6 membered heteroaryl optionally substituted withone R^(g) group, wherein the heteroaryl contains one, two, three or fourheteroatoms selected from the group consisting of O, N and S.

In certain embodiments, R² is selected from (b) C₁-C₆ alkyl optionallysubstituted with one or two groups selected from OR^(f), oxo, and NH₂,(c) C₁-C₆ alkenyl, (f) phenyl, (g) a 3 to 7 membered heterocycle,wherein the heterocycle contains one, two or three heteroatoms selectedfrom the group consisting of O, N, S, S(═O) and S(═O)₂, and (h) a 5 to 6membered heteroaryl optionally substituted with one R^(g) group, whereinthe heteroaryl contains one, two, three or four heteroatoms selectedfrom the group consisting of O, N and S. In certain embodiments, R² isselected from methyl, ethyl, CH₂OH, CH₂CH₂OH, CH₂CH(OH)CH₃,CH₂C(CH₃)₂OH, CH₂OCH₃, C(═O)OH, methylene, phenyl, pyrrolidin-2-yl,pyrrolidin-3-yl, oxazol-5-yl and 1-methyl-pyrazol-4-yl.

In certain embodiments, R² is selected from (b) C₁-C₆ alkyl optionallysubstituted with one or two groups selected from OR^(f) and oxo, (c)C₁-C₆ alkenyl, (f) phenyl, (g) a 3 to 7 membered heterocycle, whereinthe heterocycle contains one, two or three heteroatoms selected from thegroup consisting of O, N, S, S(═O) and S(═O)₂, and (h) a 5 to 6 memberedheteroaryl optionally substituted with one R^(g) group, wherein theheteroaryl contains one, two, three or four heteroatoms selected fromthe group consisting of O, N and S. In certain embodiments, R² isselected from methyl, ethyl, CH₂OH, CH₂CH₂OH, CH₂CH(OH)CH₃,CH₂C(CH₃)₂OH, CH₂OCH₃, C(═O)OH, CH₂OC(═O)C(CH₃)₂NH₂, CH₂OC(═O)CH₃,CH₂NH₂, methylene, phenyl, pyrrolidin-2-yl, pyrrolidin-3-yl, oxazol-5-yland 1-methyl-pyrazol-4-yl.

In certain embodiments, R² is selected from (a) hydrogen, (b) C₁-C₆alkyl optionally substituted with one or two groups selected fromOR^(f), oxo, and NH₂, (c) C₁-C₆ alkenyl, (f) phenyl, (g) a 3 to 7membered heterocycle, wherein the heterocycle contains one N heteroatom,and (h) a 5 to 6 membered heteroaryl optionally substituted with oneR^(g) group, wherein the heteroaryl contains one or two heteroatomsselected from the group consisting of O and N.

In certain embodiments, R² is selected from (a) hydrogen, (b) C₁-C₆alkyl optionally substituted with one or two groups selected from OR^(f)and oxo, (c) C₁-C₆ alkenyl, (f) phenyl, (g) a 3 to 7 memberedheterocycle, wherein the heterocycle contains one N heteroatom, and (h)a 5 to 6 membered heteroaryl optionally substituted with one R^(g)group, wherein the heteroaryl contains one or two heteroatoms selectedfrom the group consisting of O and N.

In certain embodiments, R² is selected from (b) C₁-C₆ alkyl optionallysubstituted with one or more groups selected from OR^(f), oxo, NH₂,NH(C₁-C₃ alkyl) and N(C₁-C₃ alkyl)₂, (f) phenyl optionally substitutedwith one or more groups selected from OR^(f) and R^(g), (g) a 3 to 7membered heterocycle optionally substituted with one or more groupsselected from OR^(f) and R^(g), wherein the heterocycle contains one,two or three heteroatoms selected from the group consisting of O, N, S,S(═O) and S(═O)₂, and (h) a 5 to 6 membered heteroaryl optionallysubstituted with one or more groups selected from OR^(f) and R^(g),wherein the heteroaryl contains one, two, three or four heteroatomsselected from the group consisting of O, N and S. In certainembodiments, R² is selected from (b) C₁-C₆ alkyl optionally substitutedwith one or two groups selected from OR^(f), oxo and NH₂, (f) phenyl,(g) a 3 to 7 membered heterocycle, wherein the heterocycle contains oneN heteroatom, and a (h) 5 to 6 membered heteroaryl optionallysubstituted with one R^(g) group, wherein the heteroaryl contains one ortwo heteroatoms selected from the group consisting of O and N. Incertain embodiments, R² is selected from methyl, ethyl, CH₂OH, CH₂CH₂OH,CH₂CH(OH)CH₃, CH₂C(CH₃)₂OH, CH₂OCH₃, C(═O)OH, CH₂OC(═O)C(CH₃)₂NH₂,CH₂OC(═O)CH₃, CH₂NH₂, phenyl, pyrrolidin-2-yl, pyrrolidin-3-yl,oxazol-5-yl and 1-methyl-pyrazol-4-yl.

In certain embodiments, R² is selected from (b) C₁-C₆ alkyl optionallysubstituted with one or more groups selected from OR^(f) and oxo, (f)phenyl optionally substituted with one or more groups selected fromOR^(f) and R^(g), (g) a 3 to 7 membered heterocycle optionallysubstituted with one or more groups selected from OR^(f) and R^(g),wherein the heterocycle contains one, two or three heteroatoms selectedfrom the group consisting of O, N, S, S(═O) and S(═O)₂, and (h) a 5 to 6membered heteroaryl optionally substituted with one or more groupsselected from OR^(f) and R^(g), wherein the heteroaryl contains one,two, three or four heteroatoms selected from the group consisting of O,N and S. In certain embodiments, R² is selected from (b) C₁-C₆ alkyloptionally substituted with one or two groups selected from OR^(f) andoxo, (f) phenyl, (g) a 3 to 7 membered heterocycle, wherein theheterocycle contains one N heteroatom, and a (h) 5 to 6 memberedheteroaryl optionally substituted with one R^(g) group, wherein theheteroaryl contains one or two heteroatoms selected from the groupconsisting of O and N. In certain embodiments, R² is selected frommethyl, ethyl, CH₂OH, CH₂CH₂OH, CH₂CH(OH)CH₃, CH₂C(CH₃)₂OH, CH₂OCH₃,C(═O)OH, phenyl, pyrrolidin-2-yl, pyrrolidin-3-yl, oxazol-5-yl and1-methyl-pyrazol-4-yl.

In certain embodiments, R² is selected from (b) C₁-C₆ alkyl optionallysubstituted with one or more groups selected from OR^(f) and oxo, (g) a3 to 7 membered heterocycle optionally substituted with one or moregroups selected from OR^(f) and R^(g), wherein the heterocycle containsone, two or three heteroatoms selected from the group consisting of O,N, S, S(═O) and S(═O)₂, and (h) a 5 to 6 membered heteroaryl optionallysubstituted with one or more groups selected from OR^(f) and R^(g),wherein the heteroaryl contains one, two, three or four heteroatomsselected from the group consisting of O, N and S. In certainembodiments, R² is selected from (b) C₁-C₆ alkyl optionally substitutedwith one or two groups selected from OR^(f) and oxo, (g) a 3 to 7membered heterocycle, wherein the heterocycle contains one N heteroatom,and a (h) 5 to 6 membered heteroaryl optionally substituted with oneR^(g) group, wherein the heteroaryl contains one or two heteroatomsselected from the group consisting of O and N. In certain embodiments,R² is selected from methyl, ethyl, CH₂OH, CH₂CH₂OH, CH₂CH(OH)CH₃,CH₂C(CH₃)₂OH, CH₂OCH₃, C(═O)OH, pyrrolidin-2-yl, pyrrolidin-3-yl,oxazol-5-yl and 1-methyl-pyrazol-4-yl.

In certain embodiments, R² is C₁-C₆ alkyl optionally substituted withone or two groups selected from OR^(f), oxo, and NH₂. In certainembodiments, R² is selected from methyl, ethyl, CH₂OH, CH₂CH₂OH,CH₂CH(OH)CH₃, CH₂C(CH₃)₂OH, CH₂OCH₃, C(═O)OH, CH₂OC(═O)C(CH₃)₂NH₂,CH₂OC(═O)CH₃ and CH₂NH₂. In certain embodiments, R² is selected fromCH₂OH, CH₂CH₂OH, CH₂CH(OH)CH₃, CH₂C(CH₃)₂OH, CH₂OCH₃,CH₂OC(═O)C(CH₃)₂NH₂, CH₂OC(═O)CH₃ and CH₂NH₂.

In certain embodiments, R² is C₁-C₆ alkyl optionally substituted withone or two groups selected from OR^(f) and oxo. In certain embodiments,R² is selected from methyl, ethyl, CH₂OH, CH₂CH₂OH, CH₂CH(OH)CH₃,CH₂C(CH₃)₂OH, CH₂OCH₃ and C(═O)OH. In certain embodiments, R² isselected from CH₂OH, CH₂CH₂OH, CH₂CH(OH)CH₃, CH₂C(CH₃)₂OH and CH₂OCH₃.

In certain embodiments, R² is C₁-C₆ alkenyl optionally substituted withone or more OR^(f) groups. In certain embodiments, R² is C₁-C₆ alkenyl.In certain embodiments, R² is methylene.

In certain embodiments, R² is phenyl optionally substituted with one ormore groups selected from OR^(f) and R^(g). In certain embodiments, R²is phenyl.

In certain embodiments, R² is a 5 to 6 membered heterocycle optionallysubstituted with one or two groups selected from OR^(f) and R^(g),wherein the heterocycle contains one, two or three heteroatoms selectedfrom the group consisting of O, N, S, S(═O) and S(═O)₂. In certainembodiments, R² is a 5 to 6 membered heterocycle, wherein theheterocycle contains one or two heteroatoms selected from the groupconsisting of O, N, S, S(═O) and S(═O)₂. In certain embodiments, R² is a5 to 6 membered heterocycle, wherein the heterocycle contains one or twoheteroatoms selected from the group consisting of O, N and S. In certainembodiments, R² is a 5 to 6 membered heterocycle, wherein theheterocycle contains one N heteroatom. In certain embodiments, R² isselected from pyrrolidin-2-yl and pyrrolidin-3-yl.

In certain embodiments, R² is a 5 to 6 membered heteroaryl optionallysubstituted with one or two groups selected from OR^(f) and R^(g),wherein the heteroaryl contains one, two, three or four heteroatomsselected from the group consisting of O, N and S. In certainembodiments, R² is a 5 to 6 membered heteroaryl optionally substitutedwith one or two groups selected from OR^(f) and R^(g), wherein theheteroaryl contains one or two heteroatoms selected from the groupconsisting of O, N and S. In certain embodiments, R² is a 5 to 6membered heteroaryl optionally substituted with one R^(g) group, whereinthe heteroaryl contains one or two heteroatoms selected from the groupconsisting of O, N and S. In certain embodiments, R² is a 5 to 6membered heteroaryl optionally substituted with one R^(g) group, whereinthe heteroaryl contains one or two heteroatoms selected from the groupconsisting of O and N. In certain embodiments, R² is selected fromoxazol-5-yl and 1-methyl-pyrazol-4-yl.

In certain embodiments, R³ is selected from (a)(CR^(h)R^(i))_(x)-phenyl, wherein the phenyl may be optionallysubstituted with one to three R^(j) groups, (b) a 5 to 6 memberedheteroaryl optionally substituted with one to three R^(j) groups, (c) a9 to 10 membered bicyclic heterocycle optionally substituted with one tothree R^(j) groups, and (d) a 9 to 10 membered bicyclic heteroaryloptionally substituted with one to three R^(j) groups.

In certain embodiments, R³ is selected from (a)(CR^(h)R^(i))_(x)-phenyl, wherein the phenyl may be optionallysubstituted with one or two R^(j) groups, (b) a 5 to 6 memberedheteroaryl optionally substituted with one or two R^(j) groups, (c) a 9to 10 membered bicyclic heterocycle optionally substituted with one ortwo R^(j) groups, and (d) a 9 to 10 membered bicyclic heteroaryloptionally substituted with one or two R^(j) groups.

In certain embodiments, R³ is selected from (a)(CR^(h)R^(i))_(x)-phenyl, wherein the phenyl may be optionallysubstituted with one or two R^(j) groups, (b) a 5 to 6 memberedheteroaryl optionally substituted with one or two R^(j) groups, whereinthe heteroaryl contains one, two, three or four heteroatoms selectedfrom O, N and S, (c) a 9 to 10 membered heterocycle optionallysubstituted with one or two R^(j) groups, wherein the heterocyclecontains one, two or three heteroatoms selected from the groupconsisting of O, N, S, S(═O) and S(═O)₂, and (d) a 9 to 10 memberedheteroaryl optionally substituted with one or two R^(j) groups, whereinthe heteroaryl contains one, two, three or four heteroatoms selectedfrom O, N and S.

In certain embodiments, each R^(j) is independently selected fromhalogen, methyl, CF₃, OCH₃, OCHF₂, CN and cyclopropyl.

In certain embodiments, R³ is selected from phenyl, 3-chlorophenyl,3-fluorophenyl, 4-chlorophenyl, 3-(trifluoromethyl)phenyl,3-methylphenyl, 3-cyanophenyl, 3-methoxyphenyl, 2-chlorophenyl,4-(difluoromethoxy)phenyl, 4-methoxyphenyl, 3,4-dichlorophenyl,2,3-difluorophenyl, 3,5-dichlorophenyl, 3,4-difluorophenyl,3,5-difluorophenyl, 2,3-dichlorophenyl, 2,4-dichlorophenyl,4-chloro-3-fluorophenyl, 3-chloro-4-fluorophenyl,3-fluoro-4-methoxyphenyl, 3-chloro-2-fluorophenyl,3-chloro-5-fluorophenyl, 4-chloro-2-fluorophenyl,5-chloro-2-fluorophenyl, 3-fluoro-5-methoxyphenyl,2-fluoro-3-methoxyphenyl, 2-fluoro-5-methoxyphenyl,3-methoxy-4-cyanophenyl, 4-chloro-3-methoxyphenyl,4-fluoro-3-methoxyphenyl, 5-chloropyridin-3-yl,1,3-dimethylpyrazol-5-yl, indolin-6-yl, indol-2-yl, indol-3-yl,indol-4-yl, indol-5-yl, indol-6-yl, indol-7-yl, 3-chloroindol-6-yl,5-chloroindol-2-yl, 3-methylindol-6-yl, 1-methylindol-6-yl,5-fluoroindol-2-yl, 2-methylindol-6-yl, 7-fluoroindol-2-yl,3-methylindol-2-yl, 3-chloroindol-2-yl, 2-methylindol-3-yl,6-chloroindol-2-yl, 3-cyclopropylindol-6-yl, 6-fluoroindol-2-yl,2,3-dimethylindol-6-yl, 4-fluoroindol-2-yl, 7-fluoroindol-6-yl,4-fluoroindol-6-yl, 5-fluoroindol-6-yl, indazol-6-yl, benzothiazol-2-yl,benzoimidazol-2-yl, 1-methylbenzoimidazol-2-yl, benzoimidazol-6-yl,benzooxazol-2-yl, 5-chlorobenzooxazol-2-yl, 6-chlorobenzooxazol-2-yl,pyrrolo[2,3-c]pyridin-2-yl, (4-methoxyphenyl)methyl,(4-fluorophenyl)methyl, (3-chlorophenyl)methyl, (4-chlorophenyl)methyl,(4-methylphenyl)methyl, (3-methoxyphenyl)methyl,(4-(trifluoromethyl)phenyl)methyl, (3-methylphenyl)methyl,(3-(trifluoromethyl)phenyl)methyl, (4-(trifluoromethoxy)phenyl)methyl,(4-cyanophenyl)methyl, (3-fluorophenyl)methyl,(3-(trifluoromethoxy)phenyl)methyl, (3,4-dichlorophenyl)methyl,(4-chloro-3-fluorophenyl)methyl and1-(4-chloro-3-fluorophenyl)-1,2-dihydroxyethyl.

In certain embodiments, R³ is selected from phenyl, 3-chlorophenyl,3-fluorophenyl, 4-chlorophenyl, 3-(trifluoromethyl)phenyl,3-methylphenyl, 3-cyanophenyl, 3-methoxyphenyl, 2-chlorophenyl,4-(difluoromethoxy)phenyl, 3,4-dichlorophenyl, 2,3-difluorophenyl,3,5-dichlorophenyl, 3,4-difluorophenyl, 3,5-difluorophenyl,2,3-dichlorophenyl, 2,4-dichlorophenyl, 4-chloro-3-fluorophenyl,3-chloro-4-fluorophenyl, 3-fluoro-4-methoxyphenyl,3-chloro-2-fluorophenyl, 3-chloro-5-fluorophenyl,4-chloro-2-fluorophenyl, 5-chloro-2-fluorophenyl,3-fluoro-5-methoxyphenyl, 2-fluoro-3-methoxyphenyl,2-fluoro-5-methoxyphenyl, 3-methoxy-4-cyanophenyl,4-chloro-3-methoxyphenyl, 5-chloropyridin-3-yl,1,3-dimethylpyrazol-5-yl, indolin-6-yl, indol-2-yl, indol-3-yl,indol-4-yl, indol-5-yl, indol-6-yl, indol-7-yl, 3-chloroindol-6-yl,5-chloroindol-2-yl, 3-methylindol-6-yl, 1-methylindol-6-yl,5-fluoroindol-2-yl, 2-methylindol-6-yl, 7-fluoroindol-2-yl,3-methylindol-2-yl, 3-chloroindol-2-yl, 2-methylindol-3-yl,6-chloroindol-2-yl, 3-cyclopropylindol-6-yl, 6-fluoroindol-2-yl,2,3-dimethylindol-6-yl, 4-fluoroindol-2-yl, 7-fluoroindol-6-yl,indazol-6-yl, benzothiazol-2-yl, benzoimidazol-2-yl,1-methylbenzoimidazol-2-yl, benzoimidazol-6-yl, benzooxazol-2-yl,5-chlorobenzooxazol-2-yl, 6-chlorobenzooxazol-2-yl,pyrrolo[2,3-c]pyridin-2-yl, (4-methoxyphenyl)methyl,(4-fluorophenyl)methyl, (3-chlorophenyl)methyl, (4-chlorophenyl)methyl,(4-methylphenyl)methyl, (3-methoxyphenyl)methyl,(4-(trifluoromethyl)phenyl)methyl, (3-methylphenyl)methyl,(3-(trifluoromethyl)phenyl)methyl, (4-(trifluoromethoxy)phenyl)methyl,(4-cyanophenyl)methyl, (3-fluorophenyl)methyl,(3-(trifluoromethoxy)phenyl)methyl, (3,4-dichlorophenyl)methyl,(4-chloro-3-fluorophenyl)methyl and1-(4-chloro-3-fluorophenyl)-1,2-dihydroxyethyl.

In certain embodiments, x is 0. In certain embodiments, R³ is selectedfrom phenyl, 3-chlorophenyl, 3-fluorophenyl, 4-chlorophenyl,3-(trifluoromethyl)phenyl, 3-methylphenyl, 3-cyanophenyl,3-methoxyphenyl, 2-chlorophenyl, 4-(difluoromethoxy)phenyl,4-methoxyphenyl, 3,4-dichlorophenyl, 2,3-difluorophenyl,3,5-dichlorophenyl, 3,4-difluorophenyl, 3,5-difluorophenyl,2,3-dichlorophenyl, 2,4-dichlorophenyl, 4-chloro-3-fluorophenyl,3-chloro-4-fluorophenyl, 3-fluoro-4-methoxyphenyl,3-chloro-2-fluorophenyl, 3-chloro-5-fluorophenyl,4-chloro-2-fluorophenyl, 5-chloro-2-fluorophenyl,3-fluoro-5-methoxyphenyl, 2-fluoro-3-methoxyphenyl,2-fluoro-5-methoxyphenyl, 3-methoxy-4-cyanophenyl,4-chloro-3-methoxyphenyl, 4-fluoro-3-methoxyphenyl,5-chloropyridin-3-yl, 1,3-dimethylpyrazol-5-yl, indolin-6-yl,indol-2-yl, indol-3-yl, indol-4-yl, indol-5-yl, indol-6-yl, indol-7-yl,3-chloroindol-6-yl, 5-chloroindol-2-yl, 3-methylindol-6-yl,1-methylindol-6-yl, 5-fluoroindol-2-yl, 2-methylindol-6-yl,7-fluoroindol-2-yl, 3-methylindol-2-yl, 3-chloroindol-2-yl,2-methylindol-3-yl, 6-chloroindol-2-yl, 3-cyclopropylindol-6-yl,6-fluoroindol-2-yl, 2,3-dimethylindol-6-yl, 4-fluoroindol-2-yl,7-fluoroindol-6-yl, 4-fluoroindol-6-yl, 5-fluoroindol-6-yl,indazol-6-yl, benzothiazol-2-yl, benzoimidazol-2-yl,1-methylbenzoimidazol-2-yl, benzoimidazol-2-yl, benzooxazol-2-yl,5-chlorobenzooxazol-2-yl, 6-chlorobenzooxazol-2-yl andpyrrolo[2,3-c]pyridin-2-yl.

In certain embodiments, x is 0. In certain embodiments, R³ is selectedfrom phenyl, 3-chlorophenyl, 3-fluorophenyl, 4-chlorophenyl,3-(trifluoromethyl)phenyl, 3-methylphenyl, 3-cyanophenyl,3-methoxyphenyl, 2-chlorophenyl, 4-(difluoromethoxy)phenyl,3,4-dichlorophenyl, 2,3-difluorophenyl, 3,5-dichlorophenyl,3,4-difluorophenyl, 3,5-difluorophenyl, 2,3-dichlorophenyl,2,4-dichlorophenyl, 4-chloro-3-fluorophenyl, 3-chloro-4-fluorophenyl,3-fluoro-4-methoxyphenyl, 3-chloro-2-fluorophenyl,3-chloro-5-fluorophenyl, 4-chloro-2-fluorophenyl,5-chloro-2-fluorophenyl, 3-fluoro-5-methoxyphenyl,2-fluoro-3-methoxyphenyl, 2-fluoro-5-methoxyphenyl,3-methoxy-4-cyanophenyl, 4-chloro-3-methoxyphenyl, 5-chloropyridin-3-yl,1,3-dimethylpyrazol-5-yl, indolin-6-yl, indol-2-yl, indol-3-yl,indol-4-yl, indol-5-yl, indol-6-yl, indol-7-yl, 3-chloroindol-6-yl,5-chloroindol-2-yl, 3-methylindol-6-yl, 1-methylindol-6-yl,5-fluoroindol-2-yl, 2-methylindol-6-yl, 7-fluoroindol-2-yl,3-methylindol-2-yl, 3-chloroindol-2-yl, 2-methylindol-3-yl,6-chloroindol-2-yl, 3-cyclopropylindol-6-yl, 6-fluoroindol-2-yl,2,3-dimethylindol-6-yl, 4-fluoroindol-2-yl, 7-fluoroindol-6-yl,indazol-6-yl, benzothiazol-2-yl, benzoimidazol-2-yl,1-methylbenzoimidazol-2-yl, benzoimidazol-2-yl, benzooxazol-2-yl,5-chlorobenzooxazol-2-yl, 6-chlorobenzooxazol-2-yl andpyrrolo[2,3-c]pyridin-2-yl.

In certain embodiments, x is 1. In certain embodiments, R^(h) and R^(i)are independently selected from hydrogen, OH and CH₂OH. In certainembodiments, R^(h) is selected from hydrogen and OH, and R¹ is selectedfrom hydrogen and CH₂OH. In certain embodiments, R^(h) is OH and R^(i)is CH₂OH, or R^(h) and R^(i) are hydrogen. In certain embodiments, R³ isselected from (4-methoxyphenyl)methyl, (4-fluorophenyl)methyl,(3-chlorophenyl)methyl, (4-chlorophenyl)methyl, (4-methylphenyl)methyl,(3-methoxyphenyl)methyl, (4-(trifluoromethyl)phenyl)methyl,(3-methylphenyl)methyl, (3-(trifluoromethyl)phenyl)methyl,(4-(trifluoromethoxy)phenyl)methyl, (4-cyanophenyl)methyl,(3-fluorophenyl)methyl, (3-(trifluoromethoxy)phenyl)methyl,(3,4-dichlorophenyl)methyl, (4-chloro-3-fluorophenyl)methyl and1-(4-chloro-3-fluorophenyl)-1,2-dihydroxyethyl.

In certain embodiments, R³ is (CR^(h)R^(i))_(x)-phenyl, wherein thephenyl may be optionally substituted with one to three R^(j) groups. Incertain embodiments, R³ is (CR^(h)R^(i))_(x)-phenyl, wherein the phenylmay be optionally substituted with one or two R^(j) groups. In certainembodiments, x is 0. In certain embodiments, R³ is phenyl optionallysubstituted with one to three R^(j) groups. In certain embodiments, R³is phenyl optionally substituted with one or two R^(j) groups. Incertain embodiments, R³ is selected from phenyl, 3-chlorophenyl,3-fluorophenyl, 4-chlorophenyl, 3-(trifluoromethyl)phenyl,3-methylphenyl, 3-cyanophenyl, 3-methoxyphenyl, 2-chlorophenyl,4-(difluoromethoxy)phenyl, 4-methoxyphenyl, 3,4-dichlorophenyl,2,3-difluorophenyl, 3,5-dichlorophenyl, 3,4-difluorophenyl,3,5-difluorophenyl, 2,3-dichlorophenyl, 2,4-dichlorophenyl,4-chloro-3-fluorophenyl, 3-chloro-4-fluorophenyl,3-fluoro-4-methoxyphenyl, 3-chloro-2-fluorophenyl,3-chloro-5-fluorophenyl, 4-chloro-2-fluorophenyl,5-chloro-2-fluorophenyl, 3-fluoro-5-methoxyphenyl,2-fluoro-3-methoxyphenyl, 2-fluoro-5-methoxyphenyl,3-methoxy-4-cyanophenyl, 4-chloro-3-methoxyphenyl and4-fluoro-3-methoxyphenyl. In certain embodiments, R³ is selected from3-chlorophenyl, 3-fluorophenyl, 4-chlorophenyl,3-(trifluoromethyl)phenyl, 3,4-dichlorophenyl, 2,3-difluorophenyl,3,4-difluorophenyl, 3,5-difluorophenyl, 4-chloro-3-fluorophenyl,3-chloro-4-fluorophenyl, 3-chloro-2-fluorophenyl and3-chloro-5-fluorophenyl. In certain embodiments, R³ is selected from3-chlorophenyl, 3-fluorophenyl, 4-chlorophenyl, 3,4-dichlorophenyl,2,3-difluorophenyl, 3,4-difluorophenyl, 3,5-difluorophenyl,4-chloro-3-fluorophenyl, 3-chloro-4-fluorophenyl,3-chloro-2-fluorophenyl and 3-chloro-5-fluorophenyl.

In certain embodiments, R³ is (CR^(h)R^(i))_(x)-phenyl, wherein thephenyl may be optionally substituted with one to three R^(j) groups. Incertain embodiments, R³ is (CR^(h)R^(i))_(x)-phenyl, wherein the phenylmay be optionally substituted with one or two R^(j) groups. In certainembodiments, x is 0. In certain embodiments, R³ is phenyl optionallysubstituted with one to three R^(j) groups. In certain embodiments, R³is phenyl optionally substituted with one or two R^(j) groups. Incertain embodiments, R³ is selected from phenyl, 3-chlorophenyl,3-fluorophenyl, 4-chlorophenyl, 3-(trifluoromethyl)phenyl,3-methylphenyl, 3-cyanophenyl, 3-methoxyphenyl, 2-chlorophenyl,4-(difluoromethoxy)phenyl, 3,4-dichlorophenyl, 2,3-difluorophenyl,3,5-dichlorophenyl, 3,4-difluorophenyl, 3,5-difluorophenyl,2,3-dichlorophenyl, 2,4-dichlorophenyl, 4-chloro-3-fluorophenyl,3-chloro-4-fluorophenyl, 3-fluoro-4-methoxyphenyl,3-chloro-2-fluorophenyl, 3-chloro-5-fluorophenyl,4-chloro-2-fluorophenyl, 5-chloro-2-fluorophenyl,3-fluoro-5-methoxyphenyl, 2-fluoro-3-methoxyphenyl,2-fluoro-5-methoxyphenyl, 3-methoxy-4-cyanophenyl and4-chloro-3-methoxyphenyl.

In certain embodiments, R³ is (CR^(h)R^(i))_(x)-phenyl, wherein thephenyl may be optionally substituted with one to three R^(j) groups. Incertain embodiments, R³ is (CR^(h)R^(i))_(x)-phenyl, wherein the phenylmay be optionally substituted with one or two R^(j) groups. In certainembodiments, x is 1. In certain embodiments, R³ is (CR^(h)R^(i))-phenyl,wherein the phenyl may be optionally substituted with one to three R^(j)groups. In certain embodiments, R³ is (CR^(h)R^(i))-phenyl, wherein thephenyl may be optionally substituted with one or two R groups. Incertain embodiments, R³ is (CH₂)-phenyl, wherein the phenyl may beoptionally substituted with one to three R^(j) groups. In certainembodiments, R³ is (CH₂)-phenyl, wherein the phenyl may be optionallysubstituted with one or two R^(j) groups.

In certain embodiments, R³ is a 5 to 6 membered heteroaryl optionallysubstituted with one to three R^(j) groups, wherein the heteroarylcontains one, two, three or four heteroatoms selected from O, N and S.In certain embodiments, R³ is a 5 to 6 membered heteroaryl optionallysubstituted with one or two R^(j) groups, wherein the heteroarylcontains one, two, three or four heteroatoms selected from O, N and S.In certain embodiments, R³ is a 5 to 6 membered heteroaryl optionallysubstituted with one or two R^(j) groups, wherein the heteroarylcontains one or two N heteroatoms. In certain embodiments, R³ isselected from 5-chloropyridin-3-yl and 1,3-dimethylpyrazol-5-yl.

In certain embodiments, R³ is a 9 to 10 membered bicyclic heterocycleoptionally substituted with one to four R^(j) groups, wherein theheterocycle contains one, two or three heteroatoms selected from thegroup consisting of O, N, S, S(═O) and S(═O)₂. In certain embodiments,R³ is a 9 to 10 membered bicyclic heterocycle optionally substitutedwith one or two R^(j) groups, wherein the heterocycle contains one, twoor three heteroatoms selected from the group consisting of O, N, S,S(═O) and S(═O)₂. In certain embodiments, R³ is a 9 to 10 memberedbicyclic heterocycle optionally substituted with one or two R^(j)groups, wherein the heterocycle contains one N heteroatom. In certainembodiments, R³ is a 9 to 10 membered bicyclic heterocycle, wherein theheterocycle contains one, two or three heteroatoms selected from thegroup consisting of O, N, S, S(═O) and S(═O)₂. In certain embodiments,R³ is a 9 to 10 membered bicyclic heterocycle, wherein the heterocyclecontains one N heteroatom. In certain embodiments, x is 0. In certainembodiments, R³ is indolin-6-yl.

In certain embodiments, R³ is a 9 to 10 membered bicyclic heteroaryloptionally substituted with one to four R^(j) groups, wherein theheteroaryl contains one, two, three or four heteroatoms selected from O,N and S. In certain embodiments, R³ is a 9 to 10 membered bicyclicheteroaryl optionally substituted with one or two R^(j) groups, whereinthe heteroaryl contains one, two, three or four heteroatoms selectedfrom O, N and S. In certain embodiments, R³ is a 9 to 10 memberedbicyclic heteroaryl optionally substituted with one or two R^(j) groups,wherein the heteroaryl contains one or two heteroatoms selected from O,N and S. In certain embodiments, x is 0. In certain embodiments, R³ isselected from indol-2-yl, indol-3-yl, indol-4-yl, indol-5-yl,indol-6-yl, indol-7-yl, 3-chloroindol-6-yl, 5-chloroindol-2-yl,3-methylindol-6-yl, 1-methylindol-6-yl, 5-fluoroindol-2-yl,2-methylindol-6-yl, 7-fluoroindol-2-yl, 3-methylindol-2-yl,3-chloroindol-2-yl, 2-methylindol-3-yl, 6-chloroindol-2-yl,3-cyclopropylindol-6-yl, 6-fluoroindol-2-yl, 2,3-dimethylindol-6-yl,4-fluoroindol-2-yl, 7-fluoroindol-6-yl, 4-fluoroindol-6-yl,5-fluoroindol-6-yl, indazol-6-yl, benzothiazol-2-yl, benzoimidazol-2-yl,1-methylbenzoimidazol-2-yl, benzoimidazol-2-yl, benzooxazol-2-yl,5-chlorobenzooxazol-2-yl, 6-chlorobenzooxazol-2-yl andpyrrolo[2,3-c]pyridin-2-yl. In certain embodiments, R³ is selected fromindol-2-yl, indol-3-yl, indol-4-yl, indol-5-yl, indol-6-yl, indol-7-yl,3-chloroindol-6-yl, 5-chloroindol-2-yl, 3-methylindol-6-yl,1-methylindol-6-yl, 5-fluoroindol-2-yl, 2-methylindol-6-yl,7-fluoroindol-2-yl, 3-methylindol-2-yl, 3-chloroindol-2-yl,2-methylindol-3-yl, 6-chloroindol-2-yl, 3-cyclopropylindol-6-yl,6-fluoroindol-2-yl, 2,3-dimethylindol-6-yl, 4-fluoroindol-2-yl,7-fluoroindol-6-yl, 4-fluoroindol-6-yl and 5-fluoroindol-6-yl. Incertain embodiments, R³ is selected from indol-2-yl, indol-3-yl,indol-4-yl, indol-5-yl, indol-6-yl, indol-7-yl, 3-chloroindol-6-yl,5-chloroindol-2-yl, 3-methylindol-6-yl, 1-methylindol-6-yl,5-fluoroindol-2-yl, 2-methylindol-6-yl, 7-fluoroindol-2-yl,3-methylindol-2-yl, 3-chloroindol-2-yl, 2-methylindol-3-yl,6-chloroindol-2-yl, 3-cyclopropylindol-6-yl, 6-fluoroindol-2-yl,2,3-dimethylindol-6-yl, 4-fluoroindol-2-yl, 4-fluoroindol-6-yl and5-fluoroindol-6-yl.

In certain embodiments, R³ is a 9 to 10 membered bicyclic heteroaryloptionally substituted with one to four R^(j) groups, wherein theheteroaryl contains one, two, three or four heteroatoms selected from O,N and S. In certain embodiments, R³ is a 9 to 10 membered bicyclicheteroaryl optionally substituted with one or two R^(j) groups, whereinthe heteroaryl contains one, two, three or four heteroatoms selectedfrom O, N and S. In certain embodiments, R³ is a 9 to 10 memberedbicyclic heteroaryl optionally substituted with one or two R^(j) groups,wherein the heteroaryl contains one or two heteroatoms selected from O,N and S. In certain embodiments, x is 0. In certain embodiments, R³ isselected from indol-2-yl, indol-3-yl, indol-4-yl, indol-5-yl,indol-6-yl, indol-7-yl, 3-chloroindol-6-yl, 5-chloroindol-2-yl,3-methylindol-6-yl, 1-methylindol-6-yl, 5-fluoroindol-2-yl,2-methylindol-6-yl, 7-fluoroindol-2-yl, 3-methylindol-2-yl,3-chloroindol-2-yl, 2-methylindol-3-yl, 6-chloroindol-2-yl,3-cyclopropylindol-6-yl, 6-fluoroindol-2-yl, 2,3-dimethylindol-6-yl,4-fluoroindol-2-yl, 7-fluoroindol-6-yl, indazol-6-yl, benzothiazol-2-yl,benzoimidazol-2-yl, 1-methylbenzoimidazol-2-yl, benzoimidazol-2-yl,benzooxazol-2-yl, 5-chlorobenzooxazol-2-yl, 6-chlorobenzooxazol-2-yl andpyrrolo[2,3-c]pyridin-2-yl. In certain embodiments, R³ is selected fromindol-2-yl, indol-3-yl, indol-4-yl, indol-5-yl, indol-6-yl, indol-7-yl,3-chloroindol-6-yl, 5-chloroindol-2-yl, 3-methylindol-6-yl,1-methylindol-6-yl, 5-fluoroindol-2-yl, 2-methylindol-6-yl,7-fluoroindol-2-yl, 3-methylindol-2-yl, 3-chloroindol-2-yl,2-methylindol-3-yl, 6-chloroindol-2-yl, 3-cyclopropylindol-6-yl,6-fluoroindol-2-yl, 2,3-dimethylindol-6-yl and 4-fluoroindol-2-yl.

In certain embodiments, R² is hydrogen and x is 1.

In certain embodiments, R² is hydrogen or C₁-C₆ alkyl optionallysubstituted with one or more groups selected from OR^(f), oxo, NH₂,NH(C₁-C₃ alkyl) and N(C₁-C₃ alkyl)₂; x is 0; and R³ is a 9 to 10membered bicyclic heterocycle optionally substituted with one or moreR^(j) groups, or a 9 to 10 membered bicyclic heteroaryl optionallysubstituted with one or more R^(j) groups. In certain embodiments, R² ishydrogen or C₁-C₆ alkyl optionally substituted with one or more groupsselected from OR^(f), oxo and NH₂; x is 0; and R³ is a 9 to 10 memberedbicyclic heterocycle optionally substituted with one or more R^(j)groups, or a 9 to 10 membered bicyclic heteroaryl optionally substitutedwith one or more R^(j) groups. In certain embodiments, R² is hydrogen orC₁-C₆ alkyl optionally substituted with one or more groups selected fromOR^(f) and oxo; x is 0; and R³ is a 9 to 10 membered bicyclicheterocycle optionally substituted with one or more R^(j) groups, or a 9to 10 membered bicyclic heteroaryl optionally substituted with one ormore R^(j) groups. In certain embodiments, R² is hydrogen or C₁-C₆alkyl; x is 0; and R³ is a 9 to 10 membered bicyclic heterocycleoptionally substituted with one or more R^(j) groups, or a 9 to 10membered bicyclic heteroaryl optionally substituted with one or moreR^(j) groups. In certain embodiments, R² is hydrogen or C₁-C₆ alkyl; xis 0; and R³ is a 9 to 10 membered bicyclic heterocycle optionallysubstituted with one to four R^(j) groups, or a 9 to 10 memberedbicyclic heteroaryl optionally substituted with one to four R^(j)groups. In certain embodiments, R² is hydrogen or methyl; x is 0; and R³is a 9 to 10 membered bicyclic heterocycle optionally substituted withone or more R^(j) groups, or a 9 to 10 membered bicyclic heteroaryloptionally substituted with one or more R^(j) groups. In certainembodiments, R² is hydrogen or methyl; x is 0; and R³ is a 9 to 10membered bicyclic heterocycle optionally substituted with one or twoR^(j) groups, or a 9 to 10 membered bicyclic heteroaryl optionallysubstituted with one or two R^(j) groups.

In certain embodiments, R¹ is selected from (d) a 3 to 7 memberedsaturated or partially unsaturated heterocycle optionally substitutedwith one to four groups independently selected from halogen, oxo, OR^(a)and C₁-C₃ alkyl optionally substituted with OR^(d), wherein theheterocycle contains one, two or three heteroatoms selected from thegroup consisting of O, N, S, S(═O) and S(═O)₂, and (e) a 5 to 6 memberedheteroaryl optionally substituted with one to four groups independentlyselected from halogen, CN, OR^(e), C₃-C₆ cycloalkyl, oxide and C₁-C₃alkyl optionally substituted with one to three groups independentlyselected from hydroxyl and halogen, wherein the heteroaryl contains one,two, three or four heteroatoms selected from the group consisting of O,N and S; R² is selected from (b) C₁-C₆ alkyl optionally substituted withone or more groups selected from OR^(f), oxo, NH₂, NH(C₁-C₃ alkyl) andN(C₁-C₃ alkyl)₂, and (h) a 5 to 6 membered heteroaryl optionallysubstituted with one or more groups selected from OR^(f) and R^(g),wherein the heteroaryl contains one, two, three or four heteroatomsselected from the group consisting of O, N and S; and R³ is phenyloptionally substituted with one or two R^(j) groups.

In certain embodiments, R¹ is selected from (d) a 3 to 7 memberedsaturated or partially unsaturated heterocycle optionally substitutedwith one to four groups independently selected from halogen, oxo, OR^(a)and C₁-C₃ alkyl optionally substituted with OR^(d), wherein theheterocycle contains one, two or three heteroatoms selected from thegroup consisting of O, N, S, S(═O) and S(═O)₂, and (e) a 5 to 6 memberedheteroaryl optionally substituted with one to four groups independentlyselected from halogen, CN, OR^(e), C₃-C₆ cycloalkyl, oxide and C₁-C₃alkyl optionally substituted with one to three groups independentlyselected from hydroxyl and halogen, wherein the heteroaryl contains one,two, three or four heteroatoms selected from the group consisting of O,N and S; R² is selected from (b) C₁-C₆ alkyl optionally substituted withone or more groups selected from OR^(f), oxo and NH₂, and (h) a 5 to 6membered heteroaryl optionally substituted with one or more groupsselected from OR^(f) and R^(g), wherein the heteroaryl contains one,two, three or four heteroatoms selected from the group consisting of O,N and S; and R³ is phenyl optionally substituted with one or two R^(j)groups.

In certain embodiments, R¹ is selected from (d) a 3 to 7 memberedsaturated or partially unsaturated heterocycle optionally substitutedwith one to four groups independently selected from halogen, oxo, OR^(a)and C₁-C₃ alkyl optionally substituted with OR^(d), wherein theheterocycle contains one, two or three heteroatoms selected from thegroup consisting of O, N, S, S(═O) and S(═O)₂, and (e) a 5 to 6 memberedheteroaryl optionally substituted with one to four groups independentlyselected from halogen, CN, OR^(e), C₃-C₆ cycloalkyl, oxide and C₁-C₃alkyl optionally substituted with one to three groups independentlyselected from hydroxyl and halogen, wherein the heteroaryl contains one,two, three or four heteroatoms selected from the group consisting of O,N and S; R² is selected from (b) C₁-C₆ alkyl optionally substituted withone or more groups selected from OR^(f) and oxo, and (h) a 5 to 6membered heteroaryl optionally substituted with one or more groupsselected from OR^(f) and R^(g), wherein the heteroaryl contains one,two, three or four heteroatoms selected from the group consisting of O,N and S; and R³ is phenyl optionally substituted with one or two R^(j)groups.

In certain embodiments, R¹ is selected from (d) a 3 to 7 memberedsaturated heterocycle optionally substituted with one or two groupsindependently selected from halogen and C₁-C₃ alkyl optionallysubstituted with OH, wherein the heterocycle contains one heteroatomselected from the group consisting of O, N and S(═O)₂, and (e) a 5 to 6membered heteroaryl optionally substituted with one to three groupsindependently selected from halogen, CN, OR^(e), cyclopropyl and C₁-C₃alkyl optionally substituted with one to three groups independentlyselected from hydroxyl and halogen, wherein the heteroaryl contains one,two or three heteroatoms selected from the group consisting of O and N;R² is selected from (b) C₁-C₆ alkyl optionally substituted with one ortwo groups selected from OR^(f), oxo, NH₂, NH(C₁-C₃ alkyl) and N(C₁-C₃alkyl)₂, and (h) a 5 to 6 membered heteroaryl optionally substitutedwith one R^(g) group, wherein the heteroaryl contains one or twoheteroatoms selected from the group consisting of O, N and S; and R³ isphenyl optionally substituted with one or two R^(j) groups.

In certain embodiments, R¹ is selected from (d) a 3 to 7 memberedsaturated heterocycle optionally substituted with one or two groupsindependently selected from halogen and C₁-C₃ alkyl optionallysubstituted with OH, wherein the heterocycle contains one heteroatomselected from the group consisting of O, N and S(═O)₂, and (e) a 5 to 6membered heteroaryl optionally substituted with one to three groupsindependently selected from halogen, CN, OR^(e), cyclopropyl and C₁-C₃alkyl optionally substituted with one to three groups independentlyselected from hydroxyl and halogen, wherein the heteroaryl contains one,two or three heteroatoms selected from the group consisting of O and N;R² is selected from (b) C₁-C₆ alkyl optionally substituted with one ortwo groups selected from OR^(f), oxo and NH₂, and (h) a 5 to 6 memberedheteroaryl optionally substituted with one R^(g) group, wherein theheteroaryl contains one or two heteroatoms selected from the groupconsisting of O, N and S; and R³ is phenyl optionally substituted withone or two R^(j) groups.

In certain embodiments, R¹ is selected from (d) a 3 to 7 memberedsaturated heterocycle optionally substituted with one or two groupsindependently selected from halogen and C₁-C₃ alkyl optionallysubstituted with OH, wherein the heterocycle contains one heteroatomselected from the group consisting of O, N and S(═O)₂, and (e) a 5 to 6membered heteroaryl optionally substituted with one to three groupsindependently selected from halogen, CN, OR^(e), cyclopropyl and C₁-C₃alkyl optionally substituted with one to three groups independentlyselected from hydroxyl and halogen, wherein the heteroaryl contains one,two or three heteroatoms selected from the group consisting of O and N;R² is selected from (b) C₁-C₆ alkyl optionally substituted with one ortwo groups selected from OR^(f) and oxo, and (h) a 5 to 6 memberedheteroaryl optionally substituted with one R^(g) group, wherein theheteroaryl contains one or two heteroatoms selected from the groupconsisting of O, N and S; and R³ is phenyl optionally substituted withone or two R^(j) groups.

In certain embodiments, R¹ is selected from tetrahydropyran-4-yl,3-fluorotetrahydropyran-4-yl, 2-(hydroxymethyl)tetrahydropyran-4-yl,1,3-dimethylpyrazol-4-yl and 1-methylpyrazol-5-yl; R² is selected fromCH₂OH, CH₂CH₂OH and 1-methyl-pyrazol-4-yl; and R³ is selected from3-chlorophenyl, 3-fluorophenyl, 4-chlorophenyl,3-(trifluoromethyl)phenyl, 3,4-dichlorophenyl, 2,3-difluorophenyl,3,4-difluorophenyl, 3,5-difluorophenyl, 4-chloro-3-fluorophenyl,3-chloro-4-fluorophenyl, 3-chloro-2-fluorophenyl and3-chloro-5-fluorophenyl.

In certain embodiments, R¹ is selected from (d) a 3 to 7 memberedsaturated or partially unsaturated heterocycle optionally substitutedwith one to four groups independently selected from halogen, oxo, OR^(a)and C₁-C₃ alkyl optionally substituted with OR^(d), wherein theheterocycle contains one, two or three heteroatoms selected from thegroup consisting of O, N, S, S(═O) and S(═O)₂, and (e) a 5 to 6 memberedheteroaryl optionally substituted with one to four groups independentlyselected from halogen, CN, OR^(e), C₃-C₆ cycloalkyl, oxide and C₁-C₃alkyl optionally substituted with one to three groups independentlyselected from hydroxyl and halogen; R² is selected from (b) C₁-C₆ alkyloptionally substituted with one or more groups selected from OR^(f),oxo, NH₂, NH(C₁-C₃ alkyl) and N(C₁-C₃ alkyl)₂, and (h) a 5 to 6 memberedheteroaryl optionally substituted with one or more groups selected fromOR^(f) and R^(g), wherein the heteroaryl contains one, two, three orfour heteroatoms selected from the group consisting of O, N and S; andR³ is a 9 to 10 membered bicyclic heteroaryl optionally substituted withone to four R^(j) groups, wherein the heteroaryl contains one, two orthree heteroatoms selected from the group consisting of O, N and S.

In certain embodiments, R¹ is selected from (d) a 3 to 7 memberedsaturated or partially unsaturated heterocycle optionally substitutedwith one to four groups independently selected from halogen, oxo, OR^(a)and C₁-C₃ alkyl optionally substituted with OR^(d), wherein theheterocycle contains one, two or three heteroatoms selected from thegroup consisting of O, N, S, S(═O) and S(═O)₂, and (e) a 5 to 6 memberedheteroaryl optionally substituted with one to four groups independentlyselected from halogen, CN, OR^(e), C₃-C₆ cycloalkyl, oxide and C₁-C₃alkyl optionally substituted with one to three groups independentlyselected from hydroxyl and halogen; R² is selected from (b) C₁-C₆ alkyloptionally substituted with one or more groups selected from OR^(f), oxoand NH₂, and (h) a 5 to 6 membered heteroaryl optionally substitutedwith one or more groups selected from OR^(f) and R^(g), wherein theheteroaryl contains one, two, three or four heteroatoms selected fromthe group consisting of O, N and S; and R³ is a 9 to 10 memberedbicyclic heteroaryl optionally substituted with one to four R^(j)groups, wherein the heteroaryl contains one, two or three heteroatomsselected from the group consisting of O, N and S.

In certain embodiments, R¹ is selected from (d) a 3 to 7 memberedsaturated or partially unsaturated heterocycle optionally substitutedwith one to four groups independently selected from halogen, oxo, OR^(a)and C₁-C₃ alkyl optionally substituted with OR^(d), wherein theheterocycle contains one, two or three heteroatoms selected from thegroup consisting of O, N, S, S(═O) and S(═O)₂, and (e) a 5 to 6 memberedheteroaryl optionally substituted with one to four groups independentlyselected from halogen, CN, OR^(e), C₃-C₆ cycloalkyl, oxide and C₁-C₃alkyl optionally substituted with one to three groups independentlyselected from hydroxyl and halogen; R² is selected from (b) C₁-C₆ alkyloptionally substituted with one or more groups selected from OR^(f) andoxo, and (h) a 5 to 6 membered heteroaryl optionally substituted withone or more groups selected from OR^(f) and R^(g), wherein theheteroaryl contains one, two, three or four heteroatoms selected fromthe group consisting of O, N and S; and R³ is a 9 to 10 memberedbicyclic heteroaryl optionally substituted with one to four R^(j)groups, wherein the heteroaryl contains one, two or three heteroatomsselected from the group consisting of O, N and S.

In certain embodiments, R¹ is selected from (d) a 3 to 7 memberedsaturated heterocycle optionally substituted with one or two groupsindependently selected from halogen and C₁-C₃ alkyl optionallysubstituted with OH, wherein the heterocycle contains one heteroatomselected from the group consisting of O, N and S(═O)₂, and (e) a 5 to 6membered heteroaryl optionally substituted with one to three groupsindependently selected from halogen, CN, OR^(e), cyclopropyl and C₁-C₃alkyl optionally substituted with one to three groups independentlyselected from hydroxyl and halogen, wherein the heteroaryl contains one,two or three heteroatoms selected from the group consisting of O and N;R² is selected from (b) C₁-C₆ alkyl optionally substituted with one ortwo groups selected from OR^(f), oxo, NH₂, NH(C₁-C₃ alkyl) and N(C₁-C₃alkyl)₂, and (h) a 5 to 6 membered heteroaryl optionally substitutedwith one R^(g) group, wherein the heteroaryl contains one or twoheteroatoms selected from the group consisting of O, N and S; and R³ isa 9 to 10 membered bicyclic heteroaryl optionally substituted with oneor two R^(j) groups, wherein the heteroaryl contains one N heteroatom.

In certain embodiments, R¹ is selected from (d) a 3 to 7 memberedsaturated heterocycle optionally substituted with one or two groupsindependently selected from halogen and C₁-C₃ alkyl optionallysubstituted with OH, wherein the heterocycle contains one heteroatomselected from the group consisting of O, N and S(═O)₂, and (e) a 5 to 6membered heteroaryl optionally substituted with one to three groupsindependently selected from halogen, CN, OR^(e), cyclopropyl and C₁-C₃alkyl optionally substituted with one to three groups independentlyselected from hydroxyl and halogen, wherein the heteroaryl contains one,two or three heteroatoms selected from the group consisting of O and N;R² is selected from (b) C₁-C₆ alkyl optionally substituted with one ortwo groups selected from OR^(f), oxo and NH₂, and (h) a 5 to 6 memberedheteroaryl optionally substituted with one R^(g) group, wherein theheteroaryl contains one or two heteroatoms selected from the groupconsisting of O, N and S; and R³ is a 9 to 10 membered bicyclicheteroaryl optionally substituted with one or two R^(j) groups, whereinthe heteroaryl contains one N heteroatom.

In certain embodiments, R¹ is selected from (d) a 3 to 7 memberedsaturated heterocycle optionally substituted with one or two groupsindependently selected from halogen and C₁-C₃ alkyl optionallysubstituted with OH, wherein the heterocycle contains one heteroatomselected from the group consisting of O, N and S(═O)₂, and (e) a 5 to 6membered heteroaryl optionally substituted with one to three groupsindependently selected from halogen, CN, OR^(e), cyclopropyl and C₁-C₃alkyl optionally substituted with one to three groups independentlyselected from hydroxyl and halogen, wherein the heteroaryl contains one,two or three heteroatoms selected from the group consisting of O and N;R² is selected from (b) C₁-C₆ alkyl optionally substituted with one ortwo groups selected from OR^(f) and oxo, and (h) a 5 to 6 memberedheteroaryl optionally substituted with one R^(g) group, wherein theheteroaryl contains one or two heteroatoms selected from the groupconsisting of O, N and S; and R³ is a 9 to 10 membered bicyclicheteroaryl optionally substituted with one or two R^(j) groups, whereinthe heteroaryl contains one N heteroatom.

In certain embodiments, R¹ is selected from tetrahydropyran-4-yl,3-fluorotetrahydropyran-4-yl, 2-(hydroxymethyl)tetrahydropyran-4-yl,1,3-dimethylpyrazol-4-yl and 1-methylpyrazol-5-yl; R² is selected fromCH₂OH, CH₂CH₂OH and 1-methyl-pyrazol-4-yl; and R³ is selected fromindol-2-yl, indol-3-yl, indol-4-yl, indol-5-yl, indol-6-yl, indol-7-yl,3-chloroindol-6-yl, 5-chloroindol-2-yl, 3-methylindol-6-yl,1-methylindol-6-yl, 5-fluoroindol-2-yl, 2-methylindol-6-yl,7-fluoroindol-2-yl, 3-methylindol-2-yl, 3-chloroindol-2-yl,2-methylindol-3-yl, 6-chloroindol-2-yl, 3-cyclopropylindol-6-yl,6-fluoroindol-2-yl, 2,3-dimethylindol-6-yl and 4-fluoroindol-2-yl.

In certain embodiments, R⁴ is selected from hydrogen, F and methyl. Incertain embodiments, R⁴ is selected from hydrogen and F. In certainembodiments, R⁴ is selected from hydrogen and methyl. In certainembodiments, R⁴ is selected from F and methyl. In certain embodiments,R⁴ is hydrogen. In certain embodiments, R⁴ is F. In certain embodiments,R⁴ is methyl.

In certain embodiments, R⁵ is selected from hydrogen, F, Cl and methyl.In certain embodiments, R⁵ is selected from hydrogen, F and methyl. Incertain embodiments, R⁵ is selected from hydrogen and F. In certainembodiments, R⁵ is selected from hydrogen and methyl. In certainembodiments, R⁵ is hydrogen. In certain embodiments, R⁵ is F. In certainembodiments, R⁵ is Cl. In certain embodiments, R⁵ is methyl.

In certain embodiments, R⁶ is selected from hydrogen and C₁-C₃ alkyl. Incertain embodiments, R⁶ is selected from hydrogen and methyl. In certainembodiments, R⁶ is hydrogen. In certain embodiments, R⁶ is methyl.

In certain embodiments, R⁷ is selected from hydrogen and halogen. Incertain embodiments, R⁷ is selected from hydrogen and F. In certainembodiments, R⁷ is hydrogen.

In certain embodiments, R⁷ is F.

In certain embodiments:

R⁵ is selected from hydrogen, halogen and C₁-C₃ alkyl; R⁶ is hydrogen;and R⁷ is hydrogen; or

R⁵ is hydrogen; R⁶ is selected from hydrogen and C₁-C₃ alkyl; and R⁷ ishydrogen; or R⁵ is hydrogen; R⁶ is hydrogen; and R⁷ is selected fromhydrogen and halogen.

In certain embodiments, a compound of Examples 1 to 323 is provided. Incertain embodiments, a compound of Examples 1 to 310 is provided.

In certain embodiments, a compound of Examples 1 to 288 and 311 to 323is provided. In certain embodiments, a compound of Examples 1 to 288 isprovided.

In certain embodiments, a compound of Formula I, II, III, IV, V, VI,VII, VIII, IX or X is provided. In certain embodiments, a compound ofFormula I, II, III, IV, V, VI, VII, VIII, IX, or X is provided, with theproviso that the compound is not Example 311 to 323.

It will be appreciated that certain compounds described herein maycontain asymmetric or chiral centers, and therefore exist in differentstereoisomeric forms. It is intended that all stereoisomeric forms ofthe compounds described herein, including but not limited to,diastereomers, enantiomers and atropisomers, as well as mixtures thereofsuch as racemic mixtures, form part of the present compounds.

In the structures shown herein, where the stereochemistry of anyparticular chiral atom is not specified, then all stereoisomers arecontemplated and included as the compounds described herein. Wherestereochemistry is specified by a solid wedge or dashed linerepresenting a particular configuration, then that stereoisomer is sospecified and defined.

It will also be appreciated that certain compounds of Formula I may beused as intermediates for further compounds of Formula I.

It will be further appreciated that the compounds described herein mayexist in unsolvated, as well as solvated forms with pharmaceuticallyacceptable solvents, such as water, ethanol, and the like, and it isintended that the compounds embrace both solvated and unsolvated forms.

Prodrugs of compounds of Formula I are not as active as the compounds ofFormula I in the assay as described in Example A (although some prodrugsmay be converted in the assay to a more active form). However, theprodrugs are capable of being converted in vivo into more activemetabolites, i.e., compounds of Formula I. Examples 290, 293, α and βare examples of prodrugs of Formula I. Prodrugs of compounds of FormulaI include compounds having Formula XI:

wherein X₁, X₂, Y₁, Y₂, R¹, R³ and R⁴ are as defined herein, and R^(pd)is OP(═O)(OH)₂ or CH₂OP(═O)(OH)₂.

Synthesis of Compounds

Compounds described herein may be synthesized by synthetic routes thatinclude processes analogous to those well-known in the chemical arts,particularly in light of the description contained herein. The startingmaterials are generally available from commercial sources such asSigma-Aldrich (St. Louis, Mo.), Alfa Aesar (Ward Hill, Mass.), or TCI(Portland, Oreg.), or are readily prepared using methods well known tothose skilled in the art (e.g., prepared by methods generally describedin Louis F. Fieser and Mary Fieser, Reagents for Organic Synthesis. v.1-23, New York: Wiley 1967-2006 ed. (also available via the WileyInterScience® website), or Beilsteins Handbuch der organischen Chemie,4, Aufl. ed. Springer-Verlag, Berlin, including supplements (alsoavailable via the Beilstein online database)).

For illustrative purposes, Schemes 1-10 show general methods forpreparing the compounds described herein, as well as key intermediates.For a more detailed description of the individual reaction steps, seethe Examples section below. Those skilled in the art will appreciatethat other synthetic routes may be used to synthesize the compounds.Although specific starting materials and reagents are depicted in theSchemes and discussed below, other starting materials and reagents canbe easily substituted to provide a variety of derivatives and/orreaction conditions. In addition, many of the compounds prepared by themethods described below can be further modified in light of thisdisclosure using conventional chemistry well known to those skilled inthe art.

Scheme 1 shows a general scheme for the synthesis of compound 1.4,wherein R⁴, R⁵, R⁶ and R⁷ are as defined herein. A 4-halo pyrimidine1.1, wherein R¹¹ 32 Cl, Br or I, may be coupled to a 4-pyridine boronicacid 1.2 with a Pd catalyst, such as PdCl₂(dppf), in the presence of abase, such as Na₂CO₃ to give intermediate 1.3. Hydrolysis of compound1.3 may be accomplished under acid conditions, such as aqueous HCl, toprovide a pyridone 1.4.

Scheme 2 shows an alternative scheme for preparing a compound 1.4,wherein R⁴, R⁵, R⁶ and R⁷ are as defined herein. A Stille coupling ofstanane 2.1 with iodopyridine 2.2, in the presence of catalysts, such asPdCl₂(PPh₃)₂ and Cu(I)I, in a suitable solvent, such asN-methyl-2-pyrrolidone (“NMP”), may be used to obtain intermediate 1.3.Hydrolysis of compound 1.3 may be accomplished under acid conditions,such as aqueous HCl, to provide a pyridone 1.4.

Scheme 3 shows a general scheme for preparing compound 3.2, wherein R²,R⁴, R⁵, R⁶, R⁷ and R^(j) are as defined herein. Pyridone 1.4 may bealkylated with a benzyl electrophile 3.1, wherein X is Cl, Br, I,mesylate ester (“OMs”) or triflate (“OTf”), in the presence of a base,such as potassium bis(trimethylsilyl)amide (“KHMDS”) or KOt-Bu with asuitable solvent, such as tetrahydrofuran (“THF”),2-methyltetrahydrofuran or dioxane, with an optional catalyst, such astetrabutylammonium iodide, to provide N-benzyl pyridone 3.2.

Scheme 4 shows an alternative scheme for preparing compound 3.2, whereinR², R⁴, R⁵, R⁶, R⁷ and R^(j) are as defined herein. Benzyl alcohol 4.1in a suitable solvent, such as THF, may be activated with diisopropylazodicarboxylate (“DIAD”) and triphenylphosphine (“PPh₃”). Subsequenttreatment with pyridone 1.4 affords N-benzyl pyridone 3.2.

Scheme 5 shows a general scheme for preparing compound 5.5, a subset of3.1, wherein R^(j) is as defined herein. Treatment of aldehyde 5.1 witha Wittig reagent, such as methyltriphenylphosphonium bromide, and abase, such as NaH, in a suitable solvent, such as THF, yields alkene5.2. Dihydroxylation of alkene 5.2 may be accomplished with Sharplesscatalyst, AD-mix-β, to afford diol 5.3. The primary hydroxyl group maybe selectively protected with tert-butyldimethylsilyl chloride (“TBSCl”)to give alcohol 5.4, which may then be converted to the correspondingmesylate 5.5 with MsCl and a base, such as triethylamine.

Scheme 6 shows an alternative route to mesylate intermediate 5.5,wherein R^(j) is as defined herein. tert-Butyldimethylsilyl-protectedester 6.1 may be converted to the Weinreb amide 6.2 usingO,N-dimethylhydroxylamine hydrochloride and isopropylmagnesium chloridein THF. A Grignard reaction of Weinreb amide 6.2 with a (substituted)phenylmagnesium bromide 6.3 in a suitable solvent, such as THF, affordsketone 6.4. Reduction of ketone 6.4 with a chiral reducing system, suchas borane-N,N,-dimethylaniline complex with catalytic(R)-2-methyl-CBS-oxazaborolidine in a suitable solvent, such as methyltert-butyl ether (“MTBE”), provides chiral alcohol 5.4. This may then beconverted to the corresponding mesylate 5.5 as in Scheme 5.

Scheme 7 shows a general scheme for preparing racemic mesylateintermediates 7.3, wherein R^(j) is as defined herein. A Grignardreaction of 7.1 and 6.3 in a solvent, such as THF, affords alcohol 7.2,which may then be reacted with MsCl to provide 7.3, a racemic version of5.5.

Scheme 8 shows a general scheme for preparing a compound 8.2, whereinR¹, R², R⁴, R⁵, R⁶, R⁷ and R^(j) are as defined herein. Compound 3.2 maybe oxidized to methyl sulfone intermediate 8.1 with an oxidant, such asmeta-chloroperoxybenzoic acid (“mCPBA”), in a suitable solvent, such asdichloromethane (“DCM”). Subsequent displacement of the methyl sulfonemoiety with amine NH₂R¹, in a suitable solvent, such as sec-BuOH,affords product 8.2.

Scheme 9 shows a general method for preparing intermediate pyridone 9.4,wherein R¹, R⁴, R⁵, R⁶ and R⁷ are as defined herein. A2,4-dichloropyrimidine 9.1 may be coupled to a 4-pyridine boronic acid1.2 with a Pd catalyst, such as PdCl₂(dppf), in the presence of a base,such as Na₂CO₃, to give intermediate 9.2. This intermediate may bereacted with an amine, NH₂R¹, in the presence of an optional base, suchas Hunig's base, in a suitable solvent, N,N-dimethylacetamide or2-butanol, either thermally or in a microwave to afford intermediate9.3. Hydrolysis of 9.3 in either aqueous acid, such as 1M HCl, or base,such as 1M NaOH, yields intermediate pyridone 9.4.

Scheme 10 shows an alternative method for preparing compound 8.2,wherein R¹, R², R⁴, R⁵, R⁶, R⁷ and R^(j) are as defined herein. Pyridone9.4 may be alkylated with benzyl electrophile 3.1, wherein X is Cl, Br,I, OMs or OTf, in the presence of a base, such as KHMDS or KOt-Bu with asuitable solvent, such as THF, 2-methyltetrahydrofuran or dioxane, withan optional catalyst, such as tetrabutylammonium iodide, to provide 8.2.

In preparing compounds of Formula I, protection of remotefunctionalities (e.g., primary or secondary amines, etc.) ofintermediates may be necessary. The need for such protection will varydepending on the nature of the remote functionality and the conditionsof the preparation methods. Suitable amino-protecting groups (NH-Pg)include acetyl, trifluoroacetyl, t-butyloxycarbonyl (“Boc”),benzyloxycarbonyl (“CBz”) and 9-fluorenylmethyleneoxycarbonyl (“Fmoc”).The need for such protection is readily determined by one skilled in theart. For a general description of protecting groups and their use, seeT. W. Greene, et al. Greene's Protective Groups in Organic Synthesis.New York: Wiley Interscience, 2006.

In certain embodiments, intermediate 1.4 is provided:

wherein R⁴, R⁵, R⁶ and R⁷ are as defined herein.

In certain embodiments, intermediate 3.2 is provided:

wherein R², R⁴, R⁵, R⁶, R⁷ and each R^(j) are as defined herein. Incertain embodiments, intermediate 3.2 is substituted with 0 to 3 R^(j)groups. In certain embodiments, intermediate 3.2 is substituted with 1or 2 R^(j) groups.

In certain embodiments, intermediate 5.5 is provided:

wherein each R^(j) is as defined herein. In certain embodiments,intermediate 5.5 is substituted with 0 to 3 R^(j) groups. In certainembodiments, intermediate 5.5 is substituted with 1 or 2 R^(j) groups.

In certain embodiments, intermediate 7.3 is provided:

wherein each R^(j) is as defined herein. In certain embodiments,intermediate 7.3 is substituted with 0 to 3 R^(j) groups. In certainembodiments, intermediate 7.3 is substituted with 1 or 2 R^(j) groups.

In certain embodiments, intermediate 8.1 is provided:

wherein R², R⁴, R⁵, R⁶, R⁷ and each R^(j) are as defined herein. Incertain embodiments, intermediate 8.1 is substituted with 0 to 3 R^(j)groups. In certain embodiments, intermediate 8.1 is substituted with 1or 2 R^(j) groups.

In certain embodiments, intermediate 9.4 is provided:

wherein R¹, R⁴, R⁵, R⁶ and R⁷ are as defined herein.

In certain embodiments, intermediate 10.1 is provided:

wherein X¹, X², Y¹, Y² and R⁴ are as defined herein.

In certain embodiments, intermediate 10.2 is provided:

wherein X¹, X², Y¹, Y², R², R³, and R⁴ are as defined herein.

In certain embodiments, intermediate 10.3 is provided:

wherein X¹, X², Y¹, Y², R², R⁴ and R^(j) are as defined herein. Incertain embodiments, intermediate 10.3 is substituted with 0 to 3 R^(j)groups. In certain embodiments, intermediate 10.3 is substituted with 1or 2 R^(j) groups.

In certain embodiments, intermediate 10.4 is provided:

wherein R³ is as defined herein.

In certain embodiments, intermediate 10.5 is provided:

wherein R³ is as defined herein.

In certain embodiments, intermediate 10.6 is provided:

wherein X₁, X₂, Y₁, Y₂, R², R³ and R⁴ are as defined herein.

In certain embodiments, intermediate 10.7 is provided:

wherein X₁, X₂, Y₁, Y₂, R², R⁴ and each R^(j) are as defined herein. Incertain embodiments, intermediate 10.7 is substituted with 0 to 3 R^(j)groups. In certain embodiments, intermediate 10.7 is substituted with 1or 2 R^(j) groups.

In certain embodiments, intermediate 10.8 is provided:

wherein X₁, X₂, Y₁, Y₂, R¹ and R⁴ are as defined herein.

In certain embodiments, a process for preparing compounds of Formula10.1 is provided, comprising:

(a) coupling a compound having the structure:

with a compound having the structure:

to prepare a compound having the structure:

and

(b) hydrolyzing the compound having the structure:

to prepare a compound of Formula 10.1:

wherein X₁, X₂, Y₁, Y₂, R⁴ and R¹¹ are as defined herein. In certainembodiments, the coupling in Step (a) is performed by a Suzuki reaction.In certain embodiments, the hydrolysis in Step (b) is performed underacidic conditions. In certain embodiments, the hydrolysis in Step (b) isperformed by addition of aqueous HCl.

In certain embodiments, a process for preparing compounds of 1.4 isprovided, comprising:

(a) coupling a compound of Formula 1.1:

with a compound of Formula 1.2:

to prepare a compound of Formula 1.3:

and

(b) hydrolyzing the compound of Formula 1.3 to prepare a compound ofFormula 1.4:

wherein R⁴, R⁵, R⁶, R⁷ and R¹¹ are as defined herein. In certainembodiments, the coupling in Step (a) is performed by a Suzuki reaction.In certain embodiments, the hydrolysis in Step (b) is performed underacidic conditions. In certain embodiments, the hydrolysis in Step (b) isperformed by addition of aqueous HCl.

In certain embodiments, a process for preparing compounds of 10.2 isprovided, comprising:

reacting a compound of Formula 10.1:

with a compound having the structure:

to prepare a compound of Formula 10.2:

wherein X₁, X₂, Y₁, Y₂, R², R³, R⁴ and X are as defined herein. Incertain embodiments, the reaction is an alkylation. In certainembodiments, the reaction takes place in the presence of a base. Incertain embodiments, the base is KHMDS or KOt-Bu. In certainembodiments, the reaction takes place in a solvent. In certainembodiments, the solvent is THF, 2-methyltetrahydrofuran or dioxane. Incertain embodiments, the reaction includes a catalyst. In certainembodiments, the catalyst is tetrabutylammonium iodide.

In certain embodiments, a process for preparing compounds of 10.3 isprovided, comprising:

reacting a compound of Formula 10.1:

with a compound of Formula 3.1:

to prepare a compound of Formula 10.3:

wherein X₁, X₂, Y₁, Y₂, R², R⁴, R^(j) and X are as defined herein. Incertain embodiments, the reaction is an alkylation. In certainembodiments, the reaction takes place in the presence of a base. Incertain embodiments, the base is KHMDS or KOt-Bu. In certainembodiments, the reaction takes place in a solvent. In certainembodiments, the solvent is THF, 2-methyltetrahydrofuran or dioxane. Incertain embodiments, the reaction includes a catalyst. In certainembodiments, the catalyst is tetrabutylammonium iodide. In certainembodiments, intermediates 3.1 and 10.3 are substituted with 0 to 3R^(j) groups. In certain embodiments, intermediate 3.1 and 10.3 aresubstituted with 1 or 2 R^(j) groups.

In certain embodiments, a process for preparing compounds of 3.2 isprovided, comprising:

reacting a compound of Formula 1.4:

with a compound of Formula 3.1:

to prepare a compound of Formula 3.2:

wherein R², R⁴, R⁵, R⁶, R⁷, R^(j) and X are as defined herein. Incertain embodiments, the reaction is an alkylation. In certainembodiments, the reaction takes place in the presence of a base. Incertain embodiments, the base is KHMDS or KOt-Bu. In certainembodiments, the reaction takes place in a solvent. In certainembodiments, the solvent is THF, 2-methyltetrahydrofuran or dioxane. Incertain embodiments, the reaction includes a catalyst. In certainembodiments, the catalyst is tetrabutylammonium iodide. In certainembodiments, intermediates 3.1 and 10.3 are substituted with 0 to 3R^(j) groups. In certain embodiments, intermediate 3.1 and 10.3 aresubstituted with 1 or 2 R^(j) groups.

In certain embodiments, a process for preparing compounds of 10.2 isprovided, comprising:

reacting a compound of Formula 10.1:

with a compound having the structure:

to prepare a compound of Formula 10.2:

wherein X₁, X₂, Y₁, Y₂, R², R³ and R⁴ are as defined herein. In certainembodiments, the reaction is a Mitsunobu reaction. In certainembodiments, the reaction includes DIAD and PPh₃. In certainembodiments, the reaction is in a solvent. In certain embodiments, thesolvent is THF.

In certain embodiments, a process for preparing compounds of 10.3 isprovided, comprising:

reacting a compound of Formula 10.1:

with a compound of Formula 4.1:

to prepare a compound of Formula 10.3:

wherein X₁, X₂, Y₁, Y₂, R², R⁴ and R^(j) are as defined herein. Incertain embodiments, the reaction is a Mitsunobu reaction. In certainembodiments, the reaction includes DIAD and PPh₃. In certainembodiments, the reaction is in a solvent. In certain embodiments, thesolvent is THF. In certain embodiments, intermediates 4.1 and 10.3 aresubstituted with 0 to 3 R^(j) groups. In certain embodiments,intermediate 4.1 and 10.3 are substituted with 1 or 2 R^(j) groups.

In certain embodiments, a process for preparing compounds of 3.2 isprovided, comprising:

reacting a compound of Formula 1.4:

with a compound of Formula 4.1:

to prepare a compound of Formula 3.2:

wherein R², R⁴, R⁵, R⁶, R⁷ and R^(j) are as defined herein. In certainembodiments, the reaction is a Mitsunobu reaction. In certainembodiments, the reaction includes DIAD and PPh₃. In certainembodiments, the reaction is in a solvent. In certain embodiments, thesolvent is THF. In certain embodiments, intermediates 4.1 and 3.2 aresubstituted with 0 to 3 R^(j) groups. In certain embodiments,intermediate 4.1 and 3.2 are substituted with 1 or 2 R^(j) groups.

In certain embodiments, a process for preparing compounds of Formula10.6 is provided, comprising:

oxidizing a compound of Formula 10.2:

to prepare a compound of Formula 10.6:

wherein X₁, X₂, Y₁, Y₂, R², R³ and R⁴ are as defined herein. In certainembodiments, the oxidation is with mCPBA. In certain embodiments, theoxidation is in a solvent. In certain embodiments, the solvent is DCM.

In certain embodiments, a process for preparing compounds of Formula10.7 is provided, comprising:

oxidizing a compound of Formula 10.3:

to prepare a compound of Formula 10.7:

wherein X₁, X₂, Y₁, Y₂, R², R⁴ and R^(j) are as defined herein. Incertain embodiments, the oxidation is with mCPBA. In certainembodiments, the oxidation is in a solvent. In certain embodiments, thesolvent is DCM. In certain embodiments, intermediates 10.3 and 10.7 aresubstituted with 0 to 3 R^(j) groups. In certain embodiments,intermediate 10.3 and 10.7 are substituted with 1 or 2 R^(j) groups.

In certain embodiments, a process for preparing compounds of Formula 8.1is provided, comprising:

oxidizing a compound of Formula 3.2:

to prepare a compound of Formula 8.1:

wherein R², R⁴, R⁵, R⁶, R⁷ and R are as defined herein. In certainembodiments, the oxidation is with mCPBA. In certain embodiments, theoxidation is in a solvent. In certain embodiments, the solvent is DCM.In certain embodiments, intermediates 3.2 and 8.1 are substituted with 0to 3 R^(j) groups. In certain embodiments, intermediate 3.2 and 8.1 aresubstituted with 1 or 2 R^(j) groups.

In certain embodiments, a process for preparing compounds of Formula10.8 is provided, comprising:

(a) coupling a compound having the structure:

with a compound having the structure:

to prepare a compound having the structure:

(b) reacting the compound having the structure:

with NH₂R¹ to prepare a compound having the structure:

and

(c) hydrolyzing the compound having the structure:

to prepare a compound of Formula 10.8:

wherein X₁, X₂, Y₁, Y₂, R¹ and R⁴ are as defined herein. In certainembodiments, the coupling in Step (a) is a Suzuki coupling. In certainembodiments, the coupling in Step (a) includes a Pd catalyst. In certainembodiments, the Pd catalyst in Step (a) is PdCl₂(dppf). In certainembodiments, the coupling in Step (a) is done in the presence of a base.In certain embodiments, the base in Step (a) is Na₂CO₃. In certainembodiments, the reaction in Step (b) is done in the presence of a base.In certain embodiments, the base in Step (b) is Hunig's base. In certainembodiments, the reaction in Step (b) is done in a solvent. In certainembodiments, the solvent in Step (b) is N,N-dimethylacetamide or2-butanol. In certain embodiments, the reaction in Step (b) is done withheat. In certain embodiments, the hydrolysis in Step (c) is done with anaqueous acid. In certain embodiments, the acid in Step (c) is HCl. Incertain embodiments, the hydrolysis in Step (c) is done with a base. Incertain embodiments, the base in Step (c) is NaOH.

In certain embodiments, a process for preparing compounds of Formula 9.4is provided, comprising:

(a) coupling a compound of Formula 9.1:

with a compound of Formula 1.2:

to prepare a compound of Formula 9.2:

(b) reacting the compound of Formula 9.2 with NH₂R¹ to prepare acompound of Formula 9.3:

and

(c) hydrolyzing the compound of Formula 9.3 to prepare a compound ofFormula 9.4:

wherein R¹, R⁴, R⁵, R⁶ and R⁷ are as defined herein. In certainembodiments, the coupling in Step (a) is a Suzuki coupling. In certainembodiments, the coupling in Step (a) includes a Pd catalyst. In certainembodiments, the Pd catalyst in Step (a) is PdCl₂(dppf). In certainembodiments, the coupling in Step (a) is done in the presence of a base.In certain embodiments, the base in Step (a) is Na₂CO₃. In certainembodiments, the reaction in Step (b) is done in the presence of a base.In certain embodiments, the base in Step (b) is Hunig's base. In certainembodiments, the reaction in Step (b) is done in a solvent. In certainembodiments, the solvent in Step (b) is N,N-dimethylacetamide or2-butanol. In certain embodiments, the reaction in Step (b) is done withheat. In certain embodiments, the hydrolysis in Step (c) is done with anaqueous acid. In certain embodiments, the acid in Step (c) is HCl. Incertain embodiments, the hydrolysis in Step (c) is done with a base. Incertain embodiments, the base in Step (c) is NaOH.

In certain embodiments, a process for preparing a compound of Formula Iis provided, comprising:

reacting a compound of Formula 10.6:

with NH₂R¹ to prepare a compound of Formula I:

wherein X₁, X₂, Y₁, Y₂, R¹, R², R³ and R⁴ are as defined herein. Incertain embodiments, the reaction is performed in a solvent. In certainembodiments, the solvent is sec-BuOH.

In certain embodiments, a process for preparing compounds of Formula Iis provided, comprising:

reacting a compound of Formula 10.8:

with a compound having the structure:

to prepare a compound of Formula I:

wherein X₁, X₂, Y₁, Y₂, R¹, R², R³, R⁴ and X are as defined herein. Incertain embodiments, the reaction is performed in the presence of abase. In certain embodiments, the base is KHMDS or KOt-Bu. In certainembodiments, the reaction is performed in a solvent. In certainembodiments, the solvent is THF, 2-methyltetrahydrofuran or dioxane. Incertain embodiments, the reaction is performed with a catalyst. Incertain embodiments, the catalyst is tetrabutylammonium iodide.

Methods of Separation

It may be advantageous to separate reaction products from one anotherand/or from starting materials. The desired products of each step orseries of steps is separated and/or purified (hereinafter separated) tothe desired degree of homogeneity by the techniques common in the art.Typically such separations involve multiphase extraction,crystallization from a solvent or solvent mixture, distillation,sublimation, or chromatography. Chromatography can involve any number ofmethods including, for example: reverse-phase and normal phase; sizeexclusion; ion exchange; high, medium and low pressure liquidchromatography methods and apparatus; small scale analytical; simulatedmoving bed (“SMB”) and preparative thin or thick layer chromatography,as well as techniques of small scale thin layer and flashchromatography. One skilled in the art will apply techniques most likelyto achieve the desired separation.

Diastereomeric mixtures can be separated into their individualdiastereomers on the basis of their physical chemical differences bymethods well known to those skilled in the art, such as bychromatography and/or fractional crystallization. Enantiomers can beseparated by converting the enantiomeric mixture into a diastereomericmixture by reaction with an appropriate optically active compound (e.g.,chiral auxiliary such as a chiral alcohol or Mosher's acid chloride),separating the diastereomers and converting (e.g., hydrolyzing) theindividual diastereoisomers to the corresponding pure enantiomers.Enantiomers can also be separated by use of a chiral HPLC column.

A single stereoisomer, e.g., an enantiomer, substantially free of itsstereoisomer may be obtained by resolution of the racemic mixture usinga method such as formation of diastereomers using optically activeresolving agents (Eliel, E. and Wilen, S. Stereochemistry of OrganicCompounds. New York: John Wiley & Sons, Inc., 1994; Lochmuller, C. H.,et al. “Chromatographic resolution of enantiomers: Selective review.” J.Chromatogr. Vol. 113, No. 3 (1975): pp. 283-302). Racemic mixtures ofchiral compounds described herein may be separated and isolated by anysuitable method, including: (1) formation of ionic, diastereomeric saltswith chiral compounds and separation by fractional crystallization orother methods, (2) formation of diastereomeric compounds with chiralderivatizing reagents, separation of the diastereomers, and conversionto the pure stereoisomers, and (3) separation of the substantially pureor enriched stereoisomers directly under chiral conditions. See: Wainer,Irving W., ed. Drug Stereochemistry: Analytical Methods andPharmacology. New York: Marcel Dekker, Inc., 1993.

Under method (1), diastereomeric salts can be formed by reaction ofenantiomerically pure chiral bases such as brucine, quinine, ephedrine,strychnine, α-methyl-β-phenylethylamine (amphetamine), and the like withasymmetric compounds bearing acidic functionality, such as carboxylicacid and sulfonic acid. The diastereomeric salts may be induced toseparate by fractional crystallization or ionic chromatography. Forseparation of the optical isomers of amino compounds, addition of chiralcarboxylic or sulfonic acids, such as camphorsulfonic acid, tartaricacid, mandelic acid, or lactic acid, can result in formation of thediastereomeric salts.

Alternatively, by method (2), the substrate to be resolved is reactedwith one enantiomer of a chiral compound to form a diastereomeric pair(Eliel, E. and Wilen, S. Stereochemistry of Organic Compounds. New York:John Wiley & Sons, Inc., 1994, p. 322). Diastereomeric compounds can beformed by reacting asymmetric compounds with enantiomerically purechiral derivatizing reagents, such as menthyl derivatives, followed byseparation of the diastereomers and hydrolysis to yield the pure orenriched enantiomer. A method of determining optical purity involvesmaking chiral esters, such as a menthyl ester, e.g., (−) menthylchloroformate in the presence of base, or Mosher ester,α-methoxy-α-(trifluoromethyl)phenyl acetate (Jacob III, Peyton.“Resolution of (±)-5-Bromonornicotine. Synthesis of (R)- and(S)-Nomicotine of High Enantiomeric Purity.” J. Org. Chem. Vol. 47, No.21 (1982): pp. 4165-4167), of the racemic mixture, and analyzing the ¹HNMR spectrum for the presence of the two atropisomeric enantiomers ordiastereomers. Stable diastereomers of atropisomeric compounds can beseparated and isolated by normal- and reverse-phase chromatographyfollowing methods for separation of atropisomeric naphthyl-isoquinolines(WO 96/15111).

By method (3), a racemic mixture of two enantiomers can be separated bychromatography using a chiral stationary phase (Lough, W. J., ed. ChiralLiquid Chromatography. New York: Chapman and Hall, 1989; Okamoto,Yoshio, et al. “Optical resolution of dihydropyridine enantiomers byhigh-performance liquid chromatography using phenylcarbamates ofpolysaccharides as a chiral stationary phase.” J. of Chromatogr. Vol.513 (1990): pp. 375-378). Enriched or purified enantiomers can bedistinguished by methods used to distinguish other chiral molecules withasymmetric carbon atoms, such as optical rotation and circulardichroism.

Biological Evaluation

Determination of the activity of ERK activity of a compound of Formula Iis possible by a number of direct and indirect detection methods.Certain exemplary compounds described herein were assayed for their ERKinhibition assay (Biological Example 1). The range of ERK bindingactivities was less than 1 nM (nanomolar) to about 10 μM (micromolar). Acell-based function assay (Biological Example 2) was used to determinethe effect of ERK inhibitors on down-stream signaling by assayingphosphorylation of P90RSK.

Administration and Pharmaceutical Formulations

The compounds described herein may be administered by any convenientroute appropriate to the condition to be treated. Suitable routesinclude oral, parenteral (including subcutaneous, intramuscular,intravenous, intraarterial, intradermal, intrathecal and epidural),transdermal, rectal, nasal, topical (including buccal and sublingual),vaginal, intraperitoneal, intrapulmonary and intranasal.

The compounds may be administered in any convenient administrative form,e.g., tablets, powders, capsules, solutions, dispersions, suspensions,syrups, sprays, suppositories, gels, emulsions, patches, etc. Suchcompositions may contain components conventional in pharmaceuticalpreparations, e.g., diluents, carriers, pH modifiers, sweeteners,bulking agents, and further active agents. If parenteral administrationis desired, the compositions will be sterile and in a solution orsuspension form suitable for injection or infusion.

A typical formulation is prepared by mixing a compound described hereinand a carrier, diluent or excipient. Suitable carriers, diluents andexcipients are well known to those skilled in the art and are describedin detail in, e.g., Ansel, Howard C., et al., Ansel's PharmaceuticalDosage Forms and Drug Delivery Systems. Philadelphia: Lippincott,Williams & Wilkins, 2004; Gennaro, Alfonso R., et al. Remington: TheScience and Practice of Pharmacy. Philadelphia: Lippincott, Williams &Wilkins, 2000; and Rowe, Raymond C. Handbook of PharmaceuticalExcipients. Chicago, Pharmaceutical Press, 2005. The formulations mayalso include one or more buffers, stabilizing agents, surfactants,wetting agents, lubricating agents, emulsifiers, suspending agents,preservatives, antioxidants, opaquing agents, glidants, processing aids,colorants, sweeteners, perfuming agents, flavoring agents, diluents andother known additives to provide an elegant presentation of the drug(i.e., a compound described herein or pharmaceutical compositionthereof) or aid in the manufacturing of the pharmaceutical product(i.e., medicament).

One embodiment includes a pharmaceutical composition comprising acompound of Formula I, II, III, IV, V, VI, VII, VIII, IX or X, or astereoisomer, tautomer or pharmaceutically acceptable salt thereof. Afurther embodiment provides a pharmaceutical composition comprising acompound of Formula I, II, III, IV, V, VI, VII, VIII, IX or X, or astereoisomer, tautomer or pharmaceutically acceptable salt thereof,together with a pharmaceutically acceptable carrier, diluent orexcipient.

Methods of Treatment with Compounds of the Invention

Also provided are methods of treating or preventing a disease orcondition by administering one or more compounds described herein, or astereoisomer, tautomer or pharmaceutically acceptable salt thereof. Inone embodiment, a method of treating a hyperproliferative disease in amammal comprising administering a therapeutically effective amount ofthe compound of Formula I, II, III, IV, V, VI, VII, VIII, IX or X, or astereoisomer, tautomer or pharmaceutically acceptable salt thereof, tothe mammal is provided.

Another embodiment provides a method of treating or preventing cancer ina mammal in need of such treatment, wherein the method comprisesadministering to said mammal a therapeutically effective amount of acompound of Formula I, II, III, IV, V, VI, VII, VIII, IX or X, or astereoisomer, tautomer or pharmaceutically acceptable salt thereof.

Another embodiment provides a method of treating or preventing pain in amammal in need of such treatment, wherein the method comprisesadministering to said mammal a therapeutically effective amount of acompound of Formula I, II, III, IV, V, VI, VII, VIII, IX or X, or astereoisomer, tautomer or pharmaceutically acceptable salt thereof.

Another embodiment provides a method of treating or preventing aninflammatory disorder in a mammal in need of such treatment, wherein themethod comprises administering to said mammal a therapeuticallyeffective amount of a compound of Formula I, II, III, IV, V, VI, VII,VIII, IX or X, or a stereoisomer, tautomer or pharmaceuticallyacceptable salt thereof.

Another embodiment provides a method of inhibiting ERK protein kinaseactivity in a cell comprising treating the cell with a compoundaccording to Formula I, II, III, IV, V, VI, VII, VIII, IX or X, or astereoisomer, tautomer or pharmaceutically acceptable salt thereof.

Another embodiment provides a method of inhibiting ERK protein kinaseactivity in a cell comprising treating the cell with a compoundaccording to Formula I, II, III, IV, V, VI, VII, VIII, IX or X, or astereoisomer, tautomer or pharmaceutically acceptable salt thereof, inan amount effective to attenuate or eliminate ERK kinase activity.

Another embodiment provides a method of inhibiting ERK protein kinaseactivity in a patient in need thereof comprising the step ofadministering to said patient a compound according to Formula I, II,III, IV, V, VI, VII, VIII, IX or X, or a stereoisomer, tautomer orpharmaceutically acceptable salt thereof.

Another embodiment provides a method of treating or ameliorating theseverity of a hyperproliferative disorder in a patient in need thereofcomprising administering to said patient a compound according to FormulaI, II, III, IV, V, VI, VII, VIII, IX or X, or a stereoisomer, tautomeror pharmaceutically acceptable salt thereof.

Another embodiment provides a method of treating or ameliorating theseverity of a hyperproliferative disorder in a patient in need thereofcomprising co-administering to said patient a compound according toFormula I, II, III, IV, V, VI, VII, VIII, IX or X, or a stereoisomer,tautomer or pharmaceutically acceptable salt thereof, with at least oneother chemotherapeutic agent used to treat or ameliorate thehyperproliferative disorder.

Another embodiment provides a method of treating or ameliorating theseverity of pain in a patient in need thereof comprising administeringto said patient a compound according to Formula I, II, III, IV, V, VI,VII, VIII, IX or X, or a stereoisomer, tautomer or pharmaceuticallyacceptable salt thereof.

Another embodiment provides a method of treating or ameliorating theseverity of an inflammatory disorder in a patient in need thereofcomprising administering to said patient a compound according to FormulaI, II, III, IV, V, VI, VII, VIII, IX or X, or a stereoisomer, tautomeror pharmaceutically acceptable salt thereof.

In another embodiment, a method of treating or preventing a disease ordisorder modulated by ERK, comprising administering to a mammal in needof such treatment an effective amount of a compound of Formula I, II,III, IV, V, VI, VII, VIII, IX or X, or a stereoisomer, tautomer orpharmaceutically acceptable salt thereof. Examples of such diseases anddisorders include, but are not limited to, hyperproliferative diseases,such as cancer, and pain or inflammatory diseases.

Another embodiment provides the use of a compound of Formula I, II, III,IV, V, VI, VII, VIII, IX or X, or a stereoisomer, tautomer orpharmaceutically acceptable salt thereof, in the manufacture of amedicament for the treatment of a hyperproliferative disease. Anotherembodiment provides the use of a compound of Formula I, II, III, IV, V,VI, VII, VIII, IX or X, or a stereoisomer, tautomer or pharmaceuticallyacceptable salt thereof, in the manufacture of a medicament for thetreatment of cancer.

Another embodiment provides the use of a compound of Formula I, II, III,IV, V, VI, VII, VIII, IX or X, or a stereoisomer, tautomer orpharmaceutically acceptable salt thereof, in the manufacture of amedicament for the treatment of pain.

Another embodiment provides the use of a compound of Formula I, II, III,IV, V, VI, VII, VIII, IX or X, or a stereoisomer, tautomer orpharmaceutically acceptable salt thereof, in the manufacture of amedicament for the treatment of an inflammatory disease.

Another embodiment provides the use of a compound of Formula I, II, III,IV, V, VI, VII, VIII, IX or X, or a stereoisomer, tautomer orpharmaceutically acceptable salt thereof, for use in the treatment ofhyperproliferative diseases. Another embodiment provides the use of acompound of Formula I, II, III, IV, V, VI, VII, VIII, IX or X, or astereoisomer, tautomer or pharmaceutically acceptable salt thereof, foruse in the treatment of cancer.

Another embodiment provides the use of a compound of Formula I, II, III,IV, V, VI, VII, VIII, IX or X, or a stereoisomer, tautomer orpharmaceutically acceptable salt thereof, for use in the treatment ofpain.

Another embodiment provides the use of a compound of Formula I, II, III,IV, V, VI, VII, VIII, IX or X, or a stereoisomer, tautomer orpharmaceutically acceptable salt thereof, for use in the treatment ofinflammatory diseases.

In certain embodiments, the hyperproliferative disease is cancer. Incertain embodiments, the cancer may be selected from breast, ovary,cervix, prostate, testis, genitourinary tract, esophagus, larynx,glioblastoma, neuroblastoma, stomach, skin, keratoacanthoma, lung,epidermoid carcinoma, large cell carcinoma, NSCLC, small cell carcinoma,lung adenocarcinoma, bone, colon, adenoma, pancreas, adenocarcinoma,thyroid, follicular carcinoma, undifferentiated carcinoma, papillarycarcinoma, seminoma, melanoma, sarcoma, bladder carcinoma, livercarcinoma and biliary passages, kidney carcinoma, myeloid disorders,lymphoid disorders, hairy cells, buccal cavity and pharynx (oral), lip,tongue, mouth, pharynx, small intestine, colon-rectum, large intestine,rectum, brain and central nervous system, Hodgkin's and leukemia. Incertain embodiments, the cancer disorder is melanoma. In certainembodiments, the cancer is pancreatic cancer. In certain embodiments,the cancer is thyroid cancer. In certain embodiments, the cancer iscolorectal cancer. In certain embodiments, the cancer is lung cancer. Incertain embodiments, the cancer is breast cancer. In certainembodiments, the cancer is ovarian cancer. In certain embodiments, thecancer is acute myelogenous leukemia. In certain embodiments, the canceris chronic myelomonocytic leukemia. In certain embodiments, the canceris chronic myelogenous leukemia. In certain embodiments, the cancer ismultiple myeloma. In certain embodiments, the cancer is myeloidleukemia.

In certain embodiments, the inflammatory disorder may be selected fromarthritis, low back pain, inflammatory bowel disease, and rheumatism.

Combination Therapy

The compounds described herein and stereoisomers, tautomers andpharmaceutically acceptable salts thereof may be employed alone or incombination with other therapeutic agents for treatment. The compoundsdescribed herein may be used in combination with one or more additionaldrugs, for example an anti-hyperproliferative (or anti-cancer) agentthat works through action on a different target protein. The secondcompound of the pharmaceutical combination formulation or dosing regimenpreferably has complementary activities to the compound describedherein, such that they do not adversely affect each other. Suchmolecules are suitably present in combination in amounts that areeffective for the purpose intended. The compounds may be administeredtogether in a unitary pharmaceutical composition or separately and, whenadministered separately this may occur simultaneously or sequentially inany order. Such sequential administration may be close in time or remotein time.

EXAMPLES

For illustrative purposes, the following Examples are included. However,it is to be understood that these Examples do not limit the inventionand are only meant to suggest a method of practicing the invention.Persons skilled in the art will recognize that the chemical reactionsdescribed may be readily adapted to prepare a number of other compoundsdescribed herein, and alternative methods for preparing the compoundsare deemed to be within the scope of this invention. For example, thesynthesis of non-exemplified compounds may be successfully performed bymodifications apparent to those skilled in the art, e.g., byappropriately protecting interfering groups, by utilizing other suitablereagents known in the art other than those described, and/or by makingroutine modifications of reaction conditions. Alternatively, otherreactions disclosed herein or known in the art will be recognized ashaving applicability for preparing other compounds described herein.

In the Examples described below, unless otherwise indicated alltemperatures are set forth in degrees Celsius. Reagents were purchasedfrom commercial suppliers such as Sigma-Aldrich, Alfa Aesar, or TCI, andwere used without further purification unless otherwise indicated.

The reactions set forth below were done generally under a positivepressure of nitrogen or argon or with a drying tube (unless otherwisestated) in anhydrous solvents, and the reaction flasks were typicallyfitted with rubber septa for the introduction of substrates and reagentsvia syringe. Glassware was oven dried and/or heat dried.

Column chromatography was done on a Biotage system (Manufacturer: DyaxCorporation) having a silica gel column or on a silica SepPak cartridge(Waters) (unless otherwise stated). ¹H NMR spectra were recorded on aVarian instrument operating at 400 MHz. ¹H-NMR spectra were obtained asCDCl₃, CD₃OD, D₂O, (CD₃)₂SO, (CD₃)₂CO, C₆D₆, CD₃CN solutions (reportedin ppm), using tetramethylsilane (0.00 ppm) or residual solvent (CDCl₃:7.26 ppm; CD₃OD: 3.31 ppm; D₂O: 4.79 ppm; (CD₃)₂SO: 2.50 ppm; (CD₃)₂CO:2.05 ppm; C₆D₆: 7.16 ppm; CD₃CN: 1.94 ppm) as the reference standard.When peak multiplicities are reported, the following abbreviations areused: s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet),br (broadened), dd (doublet of doublets), dt (doublet of triplets).Coupling constants, when given, are reported in Hertz (Hz).

Biological Example 1 ERK-2 Enzymatic Assay

Compounds were tested in an enzymatic assay using human ERK-2 (MitogenActivated Kinase 1), recombinantly expressed as an n-terminal 6-Hisfusion protein in E. coli and corresponding to aa 8-360. The substrateused was the fluorescent Omnia peptide S/T17 (Invitrogen of Carlsbad,Calif.; Cat. KNZ1171C). Test compounds were diluted in dimethylsulfoxide(“DMSO”) in 3-fold serial dilutions at 100× final concentrations. Inaddition to compound, the assay contained 50 mM HEPES [pH 7.3], 10 mMMgCl₂, 1 mM DTT, 0.005% Triton-X100, 5 nM ERK-2 enzyme, 6.25 μM S/T17peptide substrate and 25 μM ATP (corresponding to the observed K_(m))for a total reaction volume of 25 μL. The assay was run at ambienttemperature in a white 384-well polypropylene plate (Nunc, Inc ofNaperville, Ill.; Cat. 267462) collecting data every 50 seconds forapproximately 30 minutes on an Envision plate reader (PerkinElmer, Inc.of Waltham, Mass.); Excitation 340 nm/Emission 495 nm. The datacollected from each well was fit to a straight line and the resultingrates were used to calculate percent of control. Percent of control wasplotted against compound concentration and IC₅₀ values were determinedusing a four-parameter fit. Table 1 contains representative data forExamples disclosed herein. The reported IC₅₀ in Table 1 may be from asingle assay or the mean of multiple assays. Examples 1-310 were testedin the above assay and were found to have an IC₅₀ of less than 1 μM.

Biological Example 2 Cellular P90RSK(Ser380) Phosphorylation Assay

Inhibition of PMA-stimulated P90RSK(Ser380) phosphorylation wasdetermined by the following in vitro cellular mechanistic assay, whichcomprises incubating cells with a compound for 1.5 hours and quantifyingfluorescent pP90RSK(Ser380) signal on fixed cells and normalizing toGAPDH signal.

HepG2 cells were obtained from ATCC and grown in DMEM supplemented with10% fetal bovine serum. Cells were plated in 96-well plates at 35,000cells/well and allowed to attach overnight at 37° C./5% CO₂. Dilutedcompounds were then added at a final concentration of 0.5% DMSO. After1.5 hours compound incubation, cells were stimulated with the additionof phorbol 12-myristate 13-acetate (“PMA”) at a final concentration of100 ng/mL; the PMA stimulation was a 30-minute incubation at 37° C./5%CO₂. After the 30-minute PMA stimulation, cells were washed withphosphate buffered saline (“PBS”) and fixed in 3.7% formaldehyde in PBSat room temperature for 15-20 minutes. This was followed by another washin PBS and then permeabilization in 100% MeOH at room temperature for10-15 minutes. Following the permeabilization incubation, cells werewashed in PBS/0.05% Tween-20, followed by a block in Odyssey blockingbuffer (LI-COR Biosciences) for at least 1 hour. Antibodies tophosphorylated P90RSK(Ser380) (Cell Signaling #9335, rabbit monoclonal)and GAPDH (Fitzgerald 10R-G109a, mouse monoclonal) were added to thecells and incubated overnight at 4° C. pP90RSK(Ser380) antibody was usedat a 1:250 dilution; GAPDH was used at a 1:10,000 dilution. Afterwashing with PBS/0.05% Tween-20, the cells were incubated withfluorescently-labeled secondary antibodies (Anti-rabbit-Alexa Flour680,Invitrogen Cat#A21109; Anti-mouse-IRDye800CW, Rockland Inc.Cat#610-131-121) for 1 hour. Both secondary antibodies were used at a1:1000 dilution. Cells were then washed and analyzed for fluorescence atboth wavelengths using the Odyssey Infrared Imaging System (LI-CORBiosciences). Phosphorylated P90RSK(Ser380) signal was normalized toGAPDH signal. Table 1 contains representative data for Examplesdisclosed herein. The reported IC₅₀ in Table 1 may be from a singleassay or the mean of multiple assays.

Table 1 contains Examples tested in the above assays:

TABLE 1 Biological Biological Example 1 Example 2 Example # IC₅₀ (nM)IC₅₀ (nM) Example 1 3.9 31.9 Example 2 3.2 59.1 Example 3 4.0 40.3Example 4 3.8 8.5 Example 11 13.6 295.8 Example 12 51.8 931.7 Example 1415.6 842.5 Example 20 145.6 >5000 Example 21 3.0 118.5 Example 39 3.315.5 Example 42 6.3 74.0 Example 50 11.5 292.4 Example 57 35.7 1774.6Example 58 13.9 708.2 Example 60 53.0 1614.5 Example 65 6.3 67.5 Example68 3.3 185.1 Example 87 3.0 152.6 Example 102 39.5 >5000 Example 10310.4 511.0 Example 109 15.9 572.0 Example 120 3.8 86.6 Example 134 5.5543.5 Example 139 13.7 371.8 Example 157 8.7 46.3 Example 166 2.9 12.9Example 167 3.1 100.1 Example 172 2.9 12.9 Example 173 5.7 110.2 Example185 3.9 19.6 Example 209 0.8 6.7 Example 250 1.6 15.2 Example 266 2.48.6 Example 270 2.2 22 Example 289 8.5 20.4 Example 290 15.8 26.5Example 291 12.1 55.9 Example 293 9.8 16.8 Example 295 14.5 203.5Example 305 4 53 Example α 249.1 954.7 Example β 2.6 99.6

Intermediate Example A

4-(2-(methylthio)pyrimidin-4-yl)pyridin-2(1H)-one

Step A: A suspension of 4-bromo-2-(methylthio)pyrimidine (7.00 g, 34.1mmol), 2-fluoropyridin-4-ylboronic acid (5.05 g, 35.8 mmol), Na₂CO₃(10.9 g, 102 mmol) and Pd(dppf)Cl₂ CH₂Cl₂ (1.40 g, 1.71 mmol) indioxane/H₂O (100 mL; 1:1) was heated to 85° C. under an Ar balloon for 2hours. The reaction mixture was cooled to room temperature andconcentrated. The residue was diluted with ethyl acetate (200 mL) andwater (100 mL). The layers were separated, and the aqueous layer wasextracted with ethyl acetate (1×). The organics were dried, filtered andconcentrated. The crude product was purified via column chromatography,eluting with hexanes/ethyl acetate (3:1) to give4-(2-fluoropyridin-4-yl)-2-(methylthio)pyrimidine (6.83 g, 90%) as asolid. ¹H NMR (400 MHz, (CD₃)₂SO) δ 8.85 (d, J=5.2 Hz, 1H), 8.46 (d,J=5.2 Hz, 1H), 8.11 (m, 1H), 7.96 (d, J=5.2 Hz, 1H), 7.92 (s, 1H), 2.62(s, 3H); m/z (APCI-pos) M+1=222.1.

Step B: A suspension of4-(2-fluoropyridin-4-yl)-2-(methylthio)pyrimidine (6.83 g, 30.9 mmol) in2N HCl (100 mL) was heated to reflux for 2 hours. The reaction mixturewas cooled to room temperature and placed in an ice bath. The pH wasadjusted to about 7 with 2N NaOH (about 100 mL). The resulting solidswere collected by filtration, washed with water and dried to give4-(2-(methylthio)pyrimidin-4-yl)pyridin-2(1H)-one (5.07 g) as a solid.This material was placed in the thimble of a Soxhlet apparatus and wasattached to a 1 L flask charged with ethyl acetate (500 mL). Thematerial was continuously extracted for 3 days. The resulting whiteprecipitate from the ethyl acetate layer was collected by filtration(3.3 grams, 49% yield). ¹H NMR (400 MHz, (CD₃)₂SO) δ 11.85 (br, s, 1H),8.75 (d, J=5.0 Hz, 1H), 7.79 (d, J=5.0 Hz, 1H), 7.54 (d, J=7.0 Hz, 1H),7.13 (s, 1H), 6.86 (d, J=7.0 Hz, 1H), 2.58 (s, 3H); m/z (APCI-pos)M+1=220.0.

Intermediate Example B

(R)-2-(tert-butyldimethylsilyloxy)-1-(4-chloro-3-fluorophenyl)ethylmethanesulfonate

Step A: Sodium hydride (8.549 g, 213.7 mmol, 60% suspension in mineraloil) was added portionwise to a cold (0° C.) solution of4-chloro-3-fluorobenzaldehyde (26.07 g, 164.4 mmol) andmethyltriphenylphosphonium bromide (70.48 g, 197.3 mmol) in THF (400mL). The reaction mixture was allowed to warm up to room temperatureovernight. The solids were removed by filtration, and the filter cakewas washed with ether. The filtrate was concentrated (water bath about20° C.), and the residue was suspended in hexanes and stirred for 30minutes. The solids (mostly PPh₃O) were removed by filtration, and thefilter cake was washed with hexanes. The filtrate was concentrated, andthe crude product was purified by column chromatography, eluting withhexanes/ethyl acetate (25:1) to give 1-chloro-2-fluoro-4-vinylbenzene(12.1 g, 47%) as an oil. ¹H NMR (400 MHz, CDCl₃) δ 7.33 (m, 1H), 7.18(m, 1H), 7.10 (m, 1H), 6.63 (m, 1H), 5.74 (d, J=17.4 Hz, 1H), 5.32 (d,J=10.8 Hz, 1H).

Step B: 1-Chloro-2-fluoro-4-vinylbenzene (12.1 g, 77.3 mmol) was addedto a cold (0° C.) solution of AD-mix-β (108 g, 139 mmol) in t-BuOH/H₂O(600 mL; 1:1), and the mixture was allowed to warm up to roomtemperature overnight. The next day, the reaction was placed in an icebath and quenched with solid Na₂SO₃ (114 g). The mixture was stirred for1 hour and then extracted with ethyl acetate (3×500 mL). The combinedorganics were dried, filtered and concentrated to give(R)-1-(4-chloro-3-fluorophenyl)ethane-1,2-diol as an oil. The crudeproduct was used in Step C without purification.

Step C: Imidazole (13.1 g, 193 mmol) was added to a cold (0° C.)solution of (R)-1-(4-chloro-3-fluorophenyl)ethane-1,2-diol (14.7 g, 77.1mmol) in DCM (100 mL), followed by TBSCl (12.8 g, 84.8 mmol). Thereaction mixture was stirred at 0° C. for 1 hour and then quenched withwater (50 mL). The layers were separated, and the organics were dried,filtered and concentrated. The crude product was purified via columnchromatography, eluting with hexanes/ethyl acetate (100:1) to give(R)-2-(tert-butyldimethylsilyloxy)-1-(4-chloro-3-fluorophenyl)ethanol(11.0 g, 47% over two steps). ¹H NMR (400 MHz, CDCl₃) δ 7.36 (m, 1H),7.20 (m, 1H), 7.08 (m, 1H), 4.71 (m, 1H), 3.75 (m, 1H), 3.49 (m, 1H),2.96 (d, J=2.6 Hz, 1H), 0.90 (s, 9H), 0.07 (s, 3H), 0.06 (s, 3H).

Step D: Triethylamine (2.09 mL, 15.0 mmol) was added to a cold (0° C.)solution of(R)-2-(tert-butyldimethylsilyloxy)-1-(4-chloro-3-fluorophenyl)ethanol(3.05 g, 10.0 mmol) in DCM (100 mL), followed by methanesulfonylchloride (0.929 mL, 12.0 mmol). The reaction mixture was stirred at 0°C. for 30 minutes and then quenched with water (50 mL). The layers wereseparated, and the organic layer was washed with saturated NaHCO₃,dried, filtered and concentrated to give the crude product. The crudeproduct was purified via column chromatography, eluting withhexanes/ethyl acetate (25:1) to give(R)-2-(tert-butyldimethylsilyloxy)-1-(4-chloro-3-fluorophenyl)ethylmethanesulfonate (3.80 g, 99%) as an oil. ¹H NMR (400 MHz, CDCl₃) δ 7.42(m, 1H), 7.20 (m, 1H), 7.12 (m, 1H), 5.50 (m, 1H), 3.91 (m, 1H), 3.80(m, 1H), 2.98 (s, 3H), 0.88 (s, 9H), 0.05 (s, 3H), 0.04 (s, 3H).

Intermediate Example C

(S)-1-(2-(tert-butyldimethylsilyloxy)-1-(4-chloro-3-fluorophenyl)ethyl)-4-(2-(methylsulfonyl)pyrimidin-4-yl)pyridin-2(1H)-one

Step A: 1.0M KHMDS (5.09 mL, 5.09 mmol) as a solution in THF was addedto a cold (0° C.) suspension of4-(2-(methylthio)pyrimidin-4-yl)pyridin-2(1H)-one (0.93 g, 4.24 mmol) inTHF (20 mL). The reaction mixture was stirred at 0° C. for 10 minutesbefore(R)-2-(tert-butyldimethylsilyloxy)-1-(4-chloro-3-fluorophenyl)ethylmethanesulfonate (2.44 g, 6.36 mmol) was added as a solution in THF (5mL). The reaction was heated to reflux for 30 hours and then cooled toroom temperature and concentrated. The residue was taken up in ethylacetate (200 mL) and washed with water. The organics were dried,filtered and concentrated. The crude product was purified via columnchromatography, eluting with hexanes/ethyl acetate (4:1) to give(S)-1-(2-(tert-butyldimethylsilyloxy)-1-(4-chloro-3-fluorophenyl)ethyl)-4-(2-(methylthio)pyrimidin-4-yl)pyridin-2(1H)-one(1.35 g, 63%) as a solid. ¹H NMR (400 MHz, CDCl₃) δ 8.66 (d, J=5.0 Hz,1H), 7.43 (m, 2H), 7.34 (d, J=5.0 Hz, 1H), 7.32-7.28 (m, 2H), 7.16 (m,1H), 6.85 (m, 1H), 6.24 (m, 1H), 4.35 (m, 1H), 4.23 (m, 1H), 2.65 (s,3H), 0.88 (s, 9H), 0.03 (s, 3H), −0.03 (s, 3H); m/z (APCI-pos)M+1=506.1, 508.1.

Step B: mCPBA (7.1 g, 29 mmol) was added to a cold (0° C.) solution of(S)-1-(2-(tert-butyldimethylsilyloxy)-1-(4-chloro-3-fluorophenyl)ethyl)-4-(2-(methylthio)pyrimidin-4-yl)pyridin-2(1H)-one(5.8 g, 11 mmol) in DCM (100 mL), and the mixture was stirred for 2hours. The reaction mixture was washed with saturated Na₂S₂O₃ (1×),NaHCO₃ (1×), dried, filtered, and evaporated. The crude product waspurified via column chromatography, eluting with hexanes/ethyl acetate(1:1) to give(S)-1-(2-(tert-butyldimethylsilyloxy)-1-(4-chloro-3-fluorophenyl)ethyl)-4-(2-(methylsulfonyl)pyrimidin-4-yl)pyridin-2(1H)-one(5.5 g, 89%) as a solid. ¹H NMR (400 MHz, CDCl₃) δ 9.06 (d, J=5.2 Hz,1H), 7.91 (d, J=5.4 Hz, 1H), 7.55 (d, J=7.4 Hz, 1H), 7.43 (m, 1H), 7.32(d, J=2.4 Hz, 1H), 7.27 (m, 1H), 7.15 (m, 1H), 6.93 (m, 1H), 6.22 (m,1H), 4.35 (m, 1H), 4.24 (m, 1H), 3.45 (s, 3H), 0.88 (s, 9H), 0.03 (s,3H), −0.03 (s, 3H); m/z (APCI-pos) M+1=538.1, 540.0.

Intermediate Example D

(3S,4S)-3-fluorotetrahydro-2H-pyran-4-amine

Step A: 1-Chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octanebis-tetrafluoroborate (147 g, 414 mmol; Selectfluor®) was placed inacetonitrile/water (800 mL; 1:1) in a 3 L round bottom flask and cooledto 0° C. A well stirred acetonitrile (“ACN”) (120 mL) solution of4-methoxy-3,6-dihydro-2H-pyran (45.0 g, 394 mmol) was then addeddropwise. The reaction was stirred for 30 minutes under the ice bath,and then the bath was removed. The reaction was stirred for anadditional 1 hour. Solid NaCl (200 g) was then added to the reaction,along with DCM (300 mL). A saturated Na₂CO₃ solution was then addedslowly until the pH was 10. The reaction was then poured into a 4 Lseparation funnel and extracted into DCM (3×). The aqueous layer wasthen placed in a continuous liquid-liquid extractor with DCM and heatedto 58° C. for 18 hours. The combined organics were then dried (MgSO₄),filtered and concentrated at 20° C. on the rotovap to give the crudeproduct. Purification by column chromatography (500:3-500:5 DCM:MeOH)gave the product 3-fluorodihydro-2H-pyran-4(3H)-one (30 g, 64.4% yield).

Step B: 3-Fluorodihydro-2H-pyran-4(3H)-one (30 g, 254 mmol) was placedin 1,2-dichloroethane (“DCE”) (800 mL) and cooled to 0° C.Phenylmethanamine (29.8 mL, 267 mmol) was added, and the mixture wasstirred for 10 minutes. The addition of NaBH(OAc)₃ (75.4 g, 356 mmol)followed, and dropwise addition of acetic acid (14.5 mL, 254 mmol; d1.049) was then added. The reaction was stirred for 2 hours, then pouredinto 1M NaOH and extracted with DCM. The combined organic fractions weredried (MgSO₄), filtered, and concentrated to give the crude product,which was purified by reverse phase column chromatography (0-40% ACN inwater to give the racemic cis product (3S,4S)- and(3R,4R)—N-benzyl-3-fluorotetrahydro-2H-pyran-4-amine (39 g, 73.4%yield).

Step C: The enantiomers were separated by chromatography on a ChiralpakIC, 5×25 cm column eluting with 10% IPA (0.1% NH₄OH)/90% CO₂ at a flowrate of 300 mL/min and a temperature of 40° C. The back pressure was 100Bar.

Step D: (3S,4S)—N-Benzyl-3-fluorotetrahydro-2H-pyran-4-amine (3.7 g, 18mmol) was placed in MeOH (40 mL) at room temperature. Pd/C (3.8 g, 1.8mmol) was added, stirred under H₂ for 18 hours, filtered, washed withMeOH, and concentrated to give the product(3S,4S)-3-fluorotetrahydro-2H-pyran-4-amine (2.1 g, 100% yield). ¹H NMR(400 MHz, CDCl₃) δ 4.58-4.44 (m, 1H), 4.19-4.09 (m, 1H), 4.05-3.95 (m,1H), 3.56-3.38 (m, 2H), 2.96-2.84 (m, 1H), 1.88-1.77 (m, 1H), 1.72-1.65(m, 1H).

Intermediate Example E

(3S,4R)-3-fluorotetrahydro-2H-pyran-4-amine

Step A: 3-Fluorodihydro-2H-pyran-4(3H)-one (34.58 g, 292.8 mmol) wasplaced in THF (350 mL) and cooled to −78° C. L-Selectride® (307.4 mL,307.4 mmol) was then added dropwise, and the reaction was stirred for 30minutes. MeOH (35.58 mL, 878.4 mmol) and 1N NaOH (878.4 mL, 878.4 mmol)were then added, and the reaction was allowed to warm to 0° C. H₂O₂(99.59 mL, 1464 mmol) was then carefully added dropwise, and thereaction was stirred for an additional 30 minutes. A saturated brine (50mL) solution was then added, and the reaction was concentrated to removeTHF and then diluted with DCM (500 mL). The reaction was thentransferred to a liquid-liquid continuous extractor, which was heated at58° C. for 24 hours. The organic fraction was then separated, dried(MgSO₄), and concentrated to give the crude product, which was purifiedby column chromatography (5:1-3:1 DCM/ethyl acetate) to give the racemiccis product (3R,4S)- and (3S,4R)-3-fluorotetrahydro-2H-pyran-4-ol (21 g,60.2% yield).

Step B: Racemic (3R,4S)- and (3S,4R)-3-fluorotetrahydro-2H-pyran-4-ol(15.0 g, 125 mmol), isoindoline-1,3-dione (20.2 g, 137 mmol) and2-(diphenylphosphino)pyridine (42.7 g, 162 mmol) were placed in THF (550mL) at 0° C. (E)-Di-tert-butyl diazene-1,2-dicarboxylate (37.4 g, 162mmol) was added, and the reaction was then warmed to room temperaturefor 24 hours. HCl (156 mL, 624 mmol; 4M in dioxane) was added, and thereaction was stirred for 2 hours and then concentrated to dryness. Theresulting residue was dissolved in ether and washed with 4M HCl (6×).Solids that did not dissolve in ether were set aside for laterpurification (batch 1). The organics were then dried (MgSO₄), filteredand concentrated. The crude material was suspended in THF and filtered,giving solid product (batch 2). The filtrate was next concentrated, thensuspended in DCM and filtered. The solid was discarded. The filtrate wascombined with the first two batches of solids (batches 1 and 2),concentrated and purified by chromatography 500:2-500:5 DCM/MeOH to givethe racemic product2-((3S,4R)-3-fluorotetrahydro-2H-pyran-4-yl)isoindoline-1,3-dione and2-((3R,4S)-3-fluorotetrahydro-2H-pyran-4-yl)isoindoline-1,3-dione (14 g,45.0% yield).

Step C: The enantiomers were separated by chromatography on a ChiralpakIA, 5×25 cm column eluting with 10% MeOH/DCM(1:1)/90% CO₂ at a flow rateof 300 mL/min and a temperature of 40° C. The back pressure was 100 Bar.

Step D:2-((3S,4R)-3-Fluorotetrahydro-2H-pyran-4-yl)isoindoline-1,3-dione (8.4g, 34 mmol) was placed in THF/MeOH (160 mL; 1:1). Hydrazine monohydrate(17 g, 337 mmol) was then added. The reaction was stirred at 50° C. for6 hours, cooled to room temperature for 24 hours, filtered, washed withTHF and concentrated to give the crude product, which was purified bycolumn chromatography (500:20-500:25 DCM/MeOH) to give the product(3S,4R)-3-fluorotetrahydro-2H-pyran-4-amine (4.0 g, 100% yield). ¹H NMR(400 MHz, CDCl₃) δ 4.28-4.04 (m, 2H), 3.94-3.85 (m, 1H), 3.45-3.35 (m,1H), 3.30-3.20 (m, 1H), 3.05-2.92 (m, 1H), 1.97-1.88 (m, 1H), 1.58-1.48(m, 1H).

Intermediate Example F

4-(2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one

Step A: Sodium carbonate (4.91 g, 46.3 mmol) was added to2-fluoropyridin-4-ylboronic acid (2.61 g, 18.5 mmol) and2,4-dichloropyrimidine (77.2 mL, 15.4 mmol) in dioxane/water (77 mL,4:1), and the suspension was purged with argon. PdCl₂(dppf)*DCM (0.630g, 0.772 mmol) was added to the mixture, and the mixture was heated at80° C. under argon. After 3 hours, the reaction mixture was diluted withwater, and the resulting solid was collected by vacuum filtration toyield 2-chloro-4-(2-fluoropyridin-4-yl)pyrimidine (3.12 g, 14.9 mmol,96.4% yield) with minor impurities.

Step B: N-Ethyl-N-isopropylpropan-2-amine (0.496 mL, 2.86 mmol) wasadded to tetrahydro-2H-pyran-4-amine (0.265 g, 2.62 mmol) and2-chloro-4-(2-fluoropyridin-4-yl)pyrimidine (0.50 g, 2.39 mmol) in2-butanol (2 mL) in a sealed tube (microwave vial). The vial was sealedand heated at 100° C. in an oil bath overnight. The reaction mixture wasevaporated, and the dark residue was treated with ethyl acetate(“EtOAc”) and water, filtered through Celite®, and the layers wereseparated. The EtOAc was washed with brine, dried over MgSO₄, filteredand evaporated to yield a glass (0.56 g). This was chromatographed on a50 g Biotage SNAP column with 2:1 EtOAc/hexane. Fractions 28-82contained4-(2-fluoropyridin-4-yl)-N-(tetrahydro-2H-pyran-4-yl)pyrimidin-2-amine(0.32 g, 1.17 mmol, 48.9% yield).

Step C: 1M HCl (35 mL) was added to4-(2-fluoropyridin-4-yl)-N-(tetrahydro-2H-pyran-4-yl)pyrimidin-2-amine(0.32 g, 1.2 mmol). The mixture was heated at reflux overnight. Thecooled reaction mixture was neutralized with solid NaHCO₃. The resultingsolid was collected by vacuum filtration, washed into a flask withEtOAc/MeOH, evaporated and dried to afford4-(2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one(0.30 g, 1.1 mmol, 94% yield). ¹H NMR (400 MHz, (CD₃)₂SO) δ 11.74 (br s,1H), 8.40 (d, 1H), 7.48 (d, 1H), 7.33 (d, 1H), 7.11 (d, 1H), 6.99 (br s,1H), 6.85-6.76 (m, 1H), 4.04-3.92 (m, 1H), 3.92-3.85 (m, 2H), 3.45-3.36(m, 2H), 1.90-1.81 (m, 2H), 1.59-1.48 (m, 2H); m/z (APCI-pos) M+1=273.1.

Intermediate Example G

4-(5-fluoro-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one

Step A: Sodium carbonate (1.3 g, 13 mmol) to 2-fluoropyridin-4-ylboronicacid (0.71 g, 5.0 mmol) and 2,4-dichloro-5-fluoropyrimidine (0.70 g, 4.2mmol) in dioxane/water (17 mL, 4:1), and the mixture was purged withnitrogen. PdCl₂(dppf)*DCM (0.17 g, 0.21 mmol) was added to the mixture,and the sealed vial was heated at 80° C. After 1.5 hours, the cooledreaction mixture was partitioned between water and EtOAc. The EtOAc waswashed with brine, dried over MgSO₄, filtered, and evaporated to yield acrude product (1.7 g) as an oil. The crude product was absorbed onsilica gel and chromatographed on a 50 g Biotage SNAP column with 2:1hexane/EtOAc. Fractions 14-17 contained2-chloro-5-fluoro-4-(2-fluoropyridin-4-yl)pyrimidine (0.82 g, 3.6 mmol,86% yield).

Step B: N-Ethyl-N-isopropylpropan-2-amine (0.459 mL, 2.64 mmol) andtetrahydro-2H-pyran-4-amine (0.196 g, 1.93 mmol) were added to2-chloro-5-fluoro-4-(2-fluoropyridin-4-yl)pyrimidine (0.40 g, 1.76 mmol)in dimethylacetamide (“DMA”) (2 mL) in a microwave vial. The mixture washeated at 120° C. for 30 minutes in a microwave. The reaction mixturewas partitioned between EtOAc and water. The EtOAc was washed withwater, brine, dried over MgSO₄, filtered, and evaporated to yield acrude product (0.52 g) as an oil. The crude product was chromatographedon a 50 g Biotage SNAP column with 2:1 EtOAc/hexane. Fractions 14-26contained5-fluoro-4-(2-fluoropyridin-4-yl)-N-(tetrahydro-2H-pyran-4-yl)pyrimidin-2-amine(0.26 g, 0.890 mmol, 50.6% yield).

Step C: 1M HCl (15 mL) was added to5-fluoro-4-(2-fluoropyridin-4-yl)-N-(tetrahydro-2H-pyran-4-yl)pyrimidin-2-amine(0.26 g, 0.89 mmol). The suspension was heated at reflux. After 2.5hours, the suspension was neutralized with NaHCO₃, and the solid wascollected by vacuum filtration. This was suspended in MeOH andevaporated to yield4-(5-fluoro-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one(0.25 g, 0.86 mmol, 97% yield). ¹H NMR (400 MHz, (CD₃)₂SO) δ 11.80 (brs, 1H), 8.48 (d, 1H), 7.52 (d, 1H), 7.40 (d, 1H), 6.83 (br s, 1H),6.65-6.61 (m, 1H), 3.90-3.84 (m, 3H), 3.43-3.36 (m, 2H), 1.88-1.81 (m,2H), 1.57-1.46 (m, 2H); m/z (APCI-pos) M+1=291.1.

Intermediate Example H

(R)-2-((tert-butyldimethylsilyl)oxy)-1-(3-chloro-4-fluorophenyl)ethylmethanesulfonate

Step A: 2M Isopropylmagnesium chloride in THF (91.6 mL, 183 mmol) wasadded dropwise to ethyl 2-(tert-butyldimethylsilyloxy)acetate (10.0 g,45.8 mmol) and N,O-dimethylhydroxylamine hydrochloride (9.38 g, 96.2mmol) in THF (500 mL) cooled in ice. The mixture was stirred for 4.5hours allowing to slowly warm to ambient temperature. The reactionmixture was quenched with aqueous NH₄Cl and concentrated to 1/3 volume.The residue was diluted with water and extracted with EtOAc. The EtOAcwas washed with brine, dried over MgSO₄, filtered, and evaporated toyield 2-(tert-butyldimethylsilyloxy)-N-methoxy-N-methylacetamide (8.51g, 36.5 mmol, 79.6% yield) as an oil.

Step B: 0.5M (3-Chloro-4-fluorophenyl)magnesium bromide in THF (27.4 mL,13.7 mmol) was added dropwise to2-(tert-butyldimethylsilyloxy)-N-methoxy-N-methylacetamide (2.00 g, 8.57mmol) in THF (20 mL) cooled in ice. The mixture became turbid afterabout half of the Grignard reagent was added. This was stirred in an icebath for 2 hours, quenched with saturated aqueous NH₄Cl, andconcentrated to remove the THF. The aqueous residue was extracted with 2portions DCM. The combined DCM layers were dried over MgSO₄, filtered,and evaporated to yield a crude product (3.62 g) as an oil. This wastaken up in hexane and purified on a silica gel plug with hexane untilproduct started eluting, then 15:1 hexane/EtOAc. Product-containingfractions yielded2-(tert-butyldimethylsilyloxy)-1-(3-chloro-4-fluorophenyl)ethanone (2.28g, 7.53 mmol, 87.9% yield) as an oil.

Step C: Diethylaniline-borane complex (1.34 mL, 7.53 mmol) was added to1.0M (R)-1-methyl-3,3-diphenylhexahydropyrrolo[1,2-c][1,3,2]oxazaborolein toluene (0.753 mL, 0.753 mmol) in MTBE (45 mL). The mixture washeated at 40° C. for 15 minutes (the solution became cloudy), then asolution of2-(tert-butyldimethylsilyloxy)-1-(3-chloro-4-fluorophenyl)ethanone (2.28g, 7.53 mmol) in MTBE (25 mL) was added dropwise to the mixture at 40°C. The resulting mixture was heated at 40° C. for 30 minutes, cooled,and was treated with MeOH (3 mL) added dropwise. The resulting solutionwas treated with 1M HCl (10 mL), diluted with water, and extracted with2 portions DCM. The DCM was dried over MgSO₄, filtered, and evaporatedto yield a crude product as an oil. The crude product waschromatographed on a 50 g Biotage SNAP column with 50:1 hexane/EtOAc for48 fractions, then 15:1 hexane/EtOAc for 36 fractions. Fractions 40-68contained(R)-2-(tert-butyldimethylsilyloxy)-1-(3-chloro-4-fluorophenyl)ethanol(2.60 g, 8.53 mmol, 113% yield) as an oil with minor impurities.

Step D: Triethylamine (0.480 mL, 3.44 mmol) was added to(R)-2-(tert-butyldimethylsilyloxy)-1-(3-chloro-4-fluorophenyl)ethanol(0.70 g, 2.30 mmol) in DCM (10 mL) cooled in ice, and thenmethanesulfonyl chloride (0.213 mL, 2.76 mmol) was added. After 1 hour,the reaction mixture was diluted with DCM, washed with aqueous NaHCO₃,dried over MgSO₄, filtered, and evaporated to yield(R)-2-(tert-butyldimethylsilyloxy)-1-(3-chloro-4-fluorophenyl)ethylmethanesulfonate (0.87 g, 2.27 mmol, 98.9% yield) as an oil. ¹H NMR (400MHz, CDCl₃) δ 7.47-7.44 (m, 1H), 7.29-7.24 (m, 1H), 7.16 (t, 1H),5.51-5.47 (m, 1H), 3.94-3.89 (m, 1H), 3.81-3.76 (m, 1H), 2.97 (s, 3H),0.88 (s, 9H), 0.04 (d, 6H).

Intermediate Example I

2-((tert-butyldimethylsilyl)oxy)-1-(3-chloro-4-fluorophenyl)ethylmethanesulfonate

Step A: A solution of 2-(tert-butyldimethylsilyloxy)acetaldehyde (2.00g, 10.3 mmol) in dry THF (40 mL) was placed in an ice bath, and(4-chloro-3-fluorophenyl)magnesium bromide (24.8 mL, 12.4 mmol) wasadded dropwise via a syringe. The reaction mixture was stirred at 0° C.for 1 hour and then carefully quenched by dropwise addition of water.The reaction mixture was concentrated, and the residue was partitionedbetween EtOAc and saturated aqueous NH₄Cl. The organics were dried,filtered and concentrated. The crude product was purified by columnchromatography, eluting with hexanes/EtOAc (20:1) to give2-(tert-butyldimethylsilyloxy)-1-(4-chloro-3-fluorophenyl)ethanol (2.92g, 9.58 mmol, 92.8% yield) as an oil.

Step B: Triethylamine (“TEA”) (0.741 mL, 5.31 mmol; d. 0.726) was addedto a cold (0° C.) solution of2-(tert-butyldimethylsilyloxy)-1-(4-chloro-3-fluorophenyl)ethanol (1.08g, 3.54 mmol) in DCM (10 mL), followed by addition of methanesulfonylchloride (0.329 mL, 4.25 mmol). After 1 hour, the reaction mixture wasdiluted with DCM, and the organic layer was washed with saturatedaqueous NaHCO₃, dried, filtered and concentrated to afford2-(tert-butyldimethylsilyloxy)-1-(4-chloro-3-fluorophenyl)ethylmethanesulfonate (1.30 g, 3.39 mmol, 95.8% yield). ¹H NMR (400 MHz,CDCl₃) δ 7.33 (m, 1H), 7.18 (m, 1H), 7.10 (m, 1H), 6.63 (m, 1H), 5.74(d, 1H), 5.32 (d, 1H).

Intermediate Example J

(S)-3-(tert-butyldimethylsilyloxy)-1-(4-chloro-3-fluorophenyl)propylmethanesulfonate

Step A: 4-Chloro-3-fluorobenzaldehyde (15.0 g, 94.6 mmol) was combinedwith malonic acid (10.8 g, 104 mmol) and pyridine (11.5 mL, 142 mmol).The mixture was heated to 50° C. and agitated 1 hour. Then it was heatedto 100° C. and agitated 16 hours. Ice (100 g) and 6M HCl (25 mL) wereadded, and the mixture was agitated one hour. Precipitation wasfiltered, washed with water and dried in vacuo to give(E)-3-(4-chloro-3-fluorophenyl)acrylic acid (17.6 g, 87.7 mmol, 92.7%yield) as a solid.

Step B: (E)-3-(4-Chloro-3-fluorophenyl)acrylic acid (17.3 g, 86.24 mmol)was suspended in ethanol (200 mL), and chlorotrimethylsilane (24.00 mL,189.7 mmol) was added. The mixture was then agitated for 20 hours andevaporated, to give (E)-ethyl 3-(4-chloro-3-fluorophenyl)acrylate (19.65g, 85.94 mmol, 99.65% yield) as an oil, which solidified later.

Step C: (E)-Ethyl 3-(4-chloro-3-fluorophenyl)acrylate (18.3 g, 80.0mmol) was combined with toluene (200 mL) and cooled to −78° C.Diisobutylaluminium hydride (“DIBAL-H”) (100 g, 176 mmol) (25% intoluene) was then added over one hour. The reaction was then allowed toagitate and warm up to ambient temperature over 2 hours. After agitatingfor an additional hour, the reaction was quenched with ice (200 g), and6M HCl (100 mL) was added slowly. The aqueous layer was separated andextracted once with ethyl acetate. The combined organics were washedwith brine, dried and evaporated to give a waxy solid, which wastriturated with hexanes to give(E)-3-(4-chloro-3-fluorophenyl)prop-2-en-1-ol (14.0 g, 75.0 mmol, 93.7%yield) as a solid.

Step D: Diisopropyl D-tartrate (1.690 mL, 8.038 mmol) was dissolved indichloromethane (500 mL) and cooled to −20° C. Activated powdered 4 Åmolecular sieves (3 g), titanium(IV) isopropoxide (1.570 mL, 5.359 mmol)and tert-butyl hydroperoxide (19.49 mL, 107.2 mmol; in decane) wereadded sequentially, and the mixture was agitated for 1 hour at −20° C.(E)-3-(4-Chloro-3-fluorophenyl)prop-2-en-1-ol (10.0 g, 53.59 mmol) wasdissolved in dichloromethane (25 mL) and treated with 4 Å molecularsieves (1.0 g) for 1 hour. This mixture was added to the initial mixtureover 20 minutes and agitation was continued for another 3 hours at −20°C. The reaction was then quenched by addition of a mixture of asaturated NaCl solution (3 mL) and 50% w/v NaOH (3 mL). Ether was added(100 mL), and the mixture was allowed to warm up to 10° C. Afteragitating for 10 minutes at this temperature, MsSO₄ (5 g) and Celite® (2g) were added, and the mixture was agitated for an additional 15minutes. The mixture was then allowed to settle and filtered through apad of Celite®, washing with ether. Solvents were then evaporated, andresulting solid was triturated with hexane to give((2R,3R)-3-(4-chloro-3-fluorophenyl)oxiran-2-yl)methanol (10.55 g, 52.07mmol, 97.17% yield) as a solid.

Step E: ((2R,3R)-3-(4-Chloro-3-fluorophenyl)oxiran-2-yl)methanol (10.55g, 52.07 mmol) was dissolved in 1,2-dimethoxyethane (150 mL) and cooledto 0° C. Sodium bis(2-methoxyethoxy)aluminum hydride (“Red-Al”) (17.46mL, 57.28 mmol) was added dropwise. The mixture was agitated for 3 hoursat room temperature, diluted with ether (250 mL) and quenched with HClsolution (20 mL, 6M HCl+60 mL water). After agitating for 30 minutes,the aqueous phase was separated and extracted twice with ethyl acetate.The combined organics were washed with brine, dried with MgSO₄, andevaporated to give (S)-1-(4-chloro-3-fluorophenyl)propane-1,3-diol (10.5g, 51.31 mmol, 98.55% yield) as thick oil.

Step F: (S)-1-(4-Chloro-3-fluorophenyl)propane-1,3-diol (10.5 g, 51.3mmol) was dissolved in dichloromethane (200 mL), and imidazole (8.73 g,128 mmol) was added. The mixture was then cooled to 0° C., andtert-butyldimethylsilyl chloride (9.67 g, 64.1 mmol) was added. Themixture was agitated for 1 hour, diluted with dichloromethane to 250 mLand washed with water, sodium bicarbonate solution, dried andevaporated. Purified by chromatography on silica gel, eluted with 5-10%ethyl acetate/hexanes to give(S)-3-(tert-butyldimethylsilyloxy)-1-(4-chloro-3-fluorophenyl)propan-1-ol(8.40 g, 26.3 mmol, 51.3% yield) as an oil.

Step G:(S)-3-(tert-Butyldimethylsilyloxy)-1-(4-chloro-3-fluorophenyl)propan-1-ol(0.600 g, 1.88 mmol) was dissolved in dichloromethane (10 mL) and cooledto 0° C. TEA (0.393 mL, 2.82 mmol; d. 0.726) was added, followed bymethanesulfonic acid chloroanhydride (0.175 mL, 2.26 mmol), and themixture was agitated for 2 hours. The mixture was diluted withdichloromethane to 100 mL, washed with water, sodium bicarbonatesolution, dried and evaporated to give(S)-3-(tert-butyldimethylsilyloxy)-1-(4-chloro-3-fluorophenyl)propylmethanesulfonate (0.74 g, 1.86 mmol, 99.1% yield) as an oil.

Intermediate Example K

4-(6-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one

Step A: 4,6-Dichloropyrimidine (3.06 g, 20.5 mmol) was dissolved indimethylformamide (“DMF”) (20 mL) and Cs₂CO₃ (10.0 g, 30.8 mmol) wasadded. Tetrahydro-2H-pyran-4-amine (1.87 g, 18.5 mmol) combined with DMF(5 mL) was added dropwise. A slight exotherm was observed. Afteragitating at ambient temperature for 2 hours, product peak was seen inLC/MS. Agitation continued overnight. The mixture was then diluted withethyl acetate (250 mL) and washed 4 times with water, brine, dried andevaporated to give6-chloro-N-(tetrahydro-2H-pyran-4-yl)pyrimidin-4-amine (2.86 g, 13.4mmol, 65.2% yield) as a solid.

Step B: Sodium carbonate (4.24 g, 40.0 mmol) was added to2-fluoropyridin-4-ylboronic acid (2.26 g, 16.0 mmol) and6-chloro-N-(tetrahydro-2H-pyran-4-yl)pyrimidin-4-amine (2.85 g, 13.3mmol) in 4:1 dioxane/water (100 mL), and the suspension was purged withargon. PdCl₂(dppf)*DCM (0.545 g, 0.667 mmol) was added, and the mixturewas heated at 80° C. under nitrogen. After agitating for 6 hours, thereaction mixture was cooled, diluted with water and extracted with ethylacetate two times. The extract was washed with water, brine, dried andevaporated. Purified by chromatography on silica gel, eluted with 50-70%ethyl acetate/hexane to give6-(2-fluoropyridin-4-yl)-N-(tetrahydro-2H-pyran-4-yl)pyrimidin-4-amine(2.50 g, 9.11 mmol, 68.3% yield) as a solid.

Step C:6-(2-Fluoropyridin-4-yl)-N-(tetrahydro-2H-pyran-4-yl)pyrimidin-4-amine(2.50 g, 9.11 mmol) was dissolved in 1M HCl (50 mL) and heated to 90° C.The mixture was agitated overnight, cooled and neutralized with 1M NaOH(50 mL). The resulting slurry was cooled to 5° C., and the solids werefiltered off, washed with ice cold water and dried in vacuo to give4-(6-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one(2.46 g, 9.03 mmol, 99.1% yield) as a solid.

Intermediate Example L

4-(2-((tetrahydro-2H-pyran-4-yl)amino)pyridin-4-yl)pyridin-2(1H)-one

Step A: 4-Bromo-2-fluoropyridine (1.38 g, 7.84 mmol) was dissolved inDMSO (20 mL), and (tetrahydro-pyran-4-yl)amine (0.912 g, 9.02 mmol) wasadded, followed by cesium carbonate (5.11 g, 15.7 mmol). The mixture washeated to 90° C. and agitated 3 hours. After cooling, the mixture wasdiluted with ethyl acetate (200 mL) and washed with water (5 X), brine,dried and evaporated to give4-bromo-N-(tetrahydro-2H-pyran-4-yl)pyridin-2-amine (1.12 g, 4.36 mmol,55.5% yield) as an oil.

Step B: Sodium carbonate (0.989 g, 9.33 mmol) was added to2-fluoropyridin-4-ylboronic acid (0.570 g, 4.04 mmol) and4-bromo-N-(tetrahydro-2H-pyran-4-yl)pyridin-2-amine (0.80 g, 3.11 mmol)in 4:1 dioxane/water (25 mL), and the suspension was purged withnitrogen. PdCl₂(dppf)*DCM (0.127 g, 0.156 mmol) was added, and themixture was heated at 80° C. under nitrogen. After agitating for 6hours, the reaction mixture was cooled, diluted with water and extractedwith ethyl acetate (2×). The extract was washed with water, brine, driedand evaporated. Purified by chromatography on silica gel, eluted with50-70% ethyl acetate/hexane to give2′-fluoro-N-(tetrahydro-2H-pyran-4-yl)-4,4′-bipyridin-2-amine (0.64 g,2.34 mmol, 75.3% yield) as a solid.

Step C: 2′-Fluoro-N-(tetrahydro-2H-pyran-4-yl)-4,4′-bipyridin-2-amine(0.64 g, 2.3 mmol) was combined with 1M HCl (25 mL, 25 mmol) and heatedto 95° C. for 3 hours. Upon cooling, the mixture was neutralized (pH7-8) with of 1M NaOH (25 mL). The resulting slurry was cooled to 0° C.and filtered. The solids were washed with water and dried to give4-(2-(tetrahydro-2H-pyran-4-ylamino)pyridin-4-yl)pyridin-2(1H)-one (0.62g, 2.3 mmol, 98% yield) as a solid.

Intermediate Example M

cis-(4-aminotetrahydro-2H-pyran-2-yl)methanol

Step A: A solution of ZnCl (0.63 g, 4.6 mmol) in anhydrous THF (15 mL)was added to a solution of 1-methoxy-3-(trimethylsilyloxy)-1,3-butadiene(7.94 g, 46.0 mmol) and ethyl glyoxalate (7.05 g, 69.0 mmol) in toluene(30 mL) at room temperature. After stirring for 30 minutes, water (30mL) and TFA (2 mL) were added, and the mixture was stirred vigorouslyfor 20 minutes. After concentration, the residue was partitioned betweenEtOAc (200 mL) and water (100 mL). The separated organic layer waswashed with brine, dried over sodium sulfate, and concentrated to give4-oxo-3,4-dihydro-2H-pyran-2-carboxylic acid ethyl ester (8.0 g, 100%yield) as an oil, which was carried to the next step without furtherpurification. ¹H NMR (500 MHz, CDCl₃) δ 7.40 (d, J=1.0 Hz, 1H), 5.48 (d,J=6.5 Hz, 1H), 5.02 (t, J=8.0 Hz, 1H), 4.26 (q, J=7.0 Hz, 2H), 2.85 (d,J=8.0 Hz, 2H), 1.32 (t, J=7.5 Hz 3H); LCMS (ESI) m/z: 171 [M+H]⁺.

Step B: A mixture of 4-oxo-3,4-dihydro-2H-pyran-2-carboxylic acid ethylester (8.0 g, 46 mmol) and Pd/C (10%, 0.20 g) in ethyl acetate (70 mL)was stirred under hydrogen (1 atm) for 4 hours. The mixture was filteredthrough a pad of Celite®. The filtrate was concentrated, and the residuewas purified by silica gel column using 30% EtOAc in petroleum ether togive 4-oxo-tetrahydro-pyran-2-carboxylic acid ethyl ester (2.62 g, 33%yield) as an oil. ¹H NMR (500 MHz, CDCl₃) δ 4.40 (m, 1H), 4.23-4.31 (m,3H), 3.79 (m, 1H), 2.61-2.74 (m, 3H), 2.40 (d, J=15.0 Hz, 1H), 1.31 (t,J=7.5 Hz, 3H).

Step C: Ti(Oi-Pr)₄ (4.26 g, 15.0 mol) was added to a stirred solution ofethyl 4-oxo-tetrahydro-2H-pyran-2-carboxylate (1.8 g, 10 mol) in THF andCH₃OH (v/v=3:1, 100 mL). After stirring at room temperature for 1 hour,NaBH(CH₃COO)₃ (4.22 g, 20.0 mol) was added at −20° C. The reactionmixture was then kept in a refrigerator at −20° C. overnight. Ethylacetate (100 mL) was added to the reaction mixture, followed by addingbrine (2 mL) slowly. After being stirred for 30 minutes, the solid wasfiltered off, and the filtrate was concentrated to afford the crudeproduct, which was purified by silica gel column using 1% methanol inethyl acetate to give cis-ethyl4-(benzylamino)-tetrahydro-2H-pyran-2-carboxylate (1.4 g, 51% yield) asa solid. ¹H NMR (500 MHz, CDCl₃) δ 7.34-7.28 (m, 5H), 4.23 (q, J=7.0 Hz,2H), 4.17 (m, 1H), 3.94 (d, J=11.5 Hz, 2H), 3.84 (m, 1H), 3.46 (m, 1H),2.81 (m, 1H), 2.29 (d, J=10.0 Hz, 2H), 1.86 (d, J=14.5 Hz, 2H), 1.37 (m,1H), 1.29 (t, J=7.0 Hz, 3H); LCMS (ESI) m/z: 264.2 [M+H]⁺.

Step D: LiAlH₄ (1.0 g, 26 mol) was added at 0° C. to a stirred solutionof cis-ethyl 4-(benzylamino)-tetrahydro-2H-pyran-2-carboxylate (1.3 g,5.0 mol) in anhydrous THF (50 mL). After stirring for 1 hour, thereaction was quenched by slow, sequential addition of water (1 mL), 15%NaOH (1 mL), and water (3 mL). The inorganic salt was filtered off, andthe filtrated was diluted with EtOAc (50 mL), dried and concentrated togive cis-4-(benzylamino)-(tetrahydro-2H-pyran-2-yl)methanol (1.1 g, 100%yield). LCMS (ESI) m/z: 222.3 [M+H]⁺.

Step E: A mixture ofcis-4-(benzylamino)-(tetrahydro-2H-pyran-2-yl)methanol (1.1 g, 5.0 mol)and Pd/C (10%, 0.10 g) in methanol (20 mL) was stirred under hydrogen (1atm) for 2 hours. The resulting mixture was filtered through a pad ofCelite®. The filtrate was concentrated to givecis-(4-aminotetrahydro-2H-pyran-2-yl)methanol (500 mg, 77% yield). LCMS(ESI) m/z: 132.2 [M+H]⁺.

Example 1

(S)-1-(1-(4-chloro-3-fluorophenyl)-2-hydroxyethyl)-4-(2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one

Step A: A suspension of(S)-1-(2-(tert-butyldimethylsilyloxy)-1-(4-chloro-3-fluorophenyl)ethyl)-4-(2-(methylsulfonyl)pyrimidin-4-yl)pyridin-2(1H)-one(5.77 g, 10.7 mmol) and tetrahydro-2H-pyran-4-amine (2.17 g, 21.4 mmol)in sec-BuOH (30 mL) was heated to 120° C. for 4 hours in a sealed tube.The reaction mixture was cooled to room temperature and concentrated.The crude(S)-1-(2-(tert-butyldimethylsilyloxy)-1-(4-chloro-3-fluorophenyl)ethyl)-4-(2-(tetrahydro-2H-pyran-4-ylamino)pyrimidin-4-yl)pyridin-2(1H)-onewas used without purification in Step B. m/z (APCI-pos) M+1=559.2,560.2.

Step B: A solution of(S)-1-(2-(tert-butyldimethylsilyloxy)-1-(4-chloro-3-fluorophenyl)ethyl)-4-(2-(tetrahydro-2H-pyran-4-ylamino)pyrimidin-4-yl)pyridin-2(1H)-one(6.00 g, 10.7 mmol) in THF (20 mL) was treated with tetrabutyl ammoniumfluoride (12.9 mL, 12.9 mmol) at room temperature for 30 minutes. Thereaction mixture was concentrated, and the residue was taken up withethyl acetate and water. The organic layer was washed with water (1×).The combined organics were dried, filtered and concentrated. The crudeproduct was purified via column chromatography, eluting with ethylacetate to give(S)-1-(1-(4-chloro-3-fluorophenyl)-2-hydroxyethyl)-4-(2-((tetrahydro-2H-pyran-4-ylamino))pyrimidin-4-yl)pyridin-2(1H)-oneas a solid (4.14 g, 87%; 96% enantiomeric excess (“e.e.”) by chiral HPLC(Chiral Tech, column OJ-H, 4.6 mm×250 mm, 5 u, 30% ethanol/70% hexanes,1 mL/minute)). ¹H NMR (400 MHz, CDCl₃) δ 8.38 (d, J=5.0 Hz, 1H), 7.40(m, 2H), 7.20 (m, 2H), 7.10 (d, J=8.2 Hz, 1H), 6.88 (d, J=5.0 Hz, 1H),6.78 (m, 1H), 6.20 (m, 1H), 5.16 (d, J=8.0 Hz, 1H), 4.31 (m, 2H), 4.10(m, 1H), 4.00 (m, 2H), 3.55 (m, 2H), 2.74 (br, s, 1H), 2.06 (m, 2H),1.58 (m, 2H); m/z (APCI-pos) M+1=445.1, 447.0.

Example 2

1-((S)-1-(4-chloro-3-fluorophenyl)-2-hydroxyethyl-4-(2-(((3S,4S)-3-fluorotetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one

Step A: A mixture of (3S,4S)-3-fluorotetrahydro-2H-pyran-4-amine (2.8 g,24 mmol), N-ethyl-N-isopropylpropan-2-amine (2.9 g, 22 mmol) and(S)-1-(2-(tert-butyldimethylsilyloxy)-1-(4-chloro-3-fluorophenyl)ethyl)-4-(2-(methylsulfonyl)pyrimidin-4-yl)pyridin-2(1H)-one(8.0 g, 15 mmol) in sec-BuOH (25 mL) was placed in a sealed tube andheated to 120° C. for 68 hours. The reaction mixture was cooled to roomtemperature and concentrated. The crude1-((S)-2-(tert-butyldimethylsilyloxy)-1-(4-chloro-3-fluorophenyl)ethyl)-4-(2-((3S,4S)-3-fluorotetrahydro-2H-pyran-4-ylamino)pyrimidin-4-yl)pyridin-2(1H)-onewas used in Step B without purification. m/z (APCI-pos) M+1=577.2,579.2.

Step B: A 4.0M solution of hydrogen chloride (18.6 mL, 74.5 mmol) indioxane was slowly added to a cold (0° C.) solution of1-((S)-2-(tert-butyldimethylsilyloxy)-1-(4-chloro-3-fluorophenyl)ethyl)-4-(2-((3S,4S)-3-fluorotetrahydro-2H-pyran-4-ylamino)pyrimidin-4-yl)pyridin-2(1H)-one(8.6 g, 14.9 mmol) in MeOH (40 mL), and the mixture was stirred for 1hour. The reaction mixture was concentrated, and the residue was takenup in saturated NaHCO₃ and extracted with ethyl acetate (2×). Theorganic layer was dried, filtered and concentrated. The crude productwas purified by column chromatography, eluting with hexanes/ethylacetate (1:4) to give1-((S)-1-(4-chloro-3-fluorophenyl)-2-hydroxyethyl)-4-(2-(((3S,4S)-3-fluorotetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-oneas a solid (4.58 g, 66%; 97% e.e. by chiral HPLC (Chiral Tech, columnOD-H, 4.6 mm×250 mm, 5 u, 30% ethanol/70% hexanes, 1 mL/minute)). ¹H NMR(400 MHz, CDCl₃) δ 8.38 (d, J=5.0 Hz, 1H), 7.41 (m, 2H), 7.21-7.09 (m,3H), 6.89 (d, J=5.0 Hz, 1H), 6.76 (d, J=7.0 Hz, 1H), 6.20 (m, 1H), 5.55(d, J=8.2 Hz, 1H), 4.75 (d, J=50 Hz, 1H), 4.38-4.18 (m, 4H), 4.05 (m,1H), 3.69-3.53 (m, 2H), 3.12 (br, s, 1H), 2.08-1.84 (m, 2H); m/z(APCI-pos) M+1=463.1, 465.0.

Example 3

1-((S)-1-(4-chloro-3-fluorophenyl)-2-hydroxyethyl)-4-(2-(((3S,4R)-3-fluorotetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one

Step A:1-((S)-2-(tert-Butyldimethylsilyloxy)-1-(4-chloro-3-fluorophenyl)ethyl)-4-(2-((3S,4R)-3-fluorotetrahydro-2H-pyran-4-ylamino)pyrimidin-4-yl)pyridin-2(1H)-onewas prepared according to the general procedure of Example 2, Step A,substituting (3S,4R)-3-fluorotetrahydro-2H-pyran-4-amine for(3S,4S)-3-fluorotetrahydro-2H-pyran-4-amine. m/z (APCI-pos) M+1=577.2,579.2.

Step B:1-((S)-1-(4-Chloro-3-fluorophenyl)-2-hydroxyethyl)-4-(2-((3S,4R)-3-fluorotetrahydro-2H-pyran-4-ylamino)pyrimidin-4-yl)pyridin-2(1H)-one(56%, 2 steps; 96% e.e. by chiral HPLC (Chiral Tech, column OJ-H, 4.6mm×250 mm, 5 u, 20% ethanol/80% hexanes, 1 mL/minute)) was preparedaccording to the general procedure of Example 2, Step B, substituting1-((S)-2-(tert-butyldimethylsilyloxy)-1-(4-chloro-3-fluorophenyl)ethyl)-4-(2-(((3S,4R)-3-fluorotetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-onefor1-((S)-2-(tert-butyldimethylsilyloxy)-1-(4-chloro-3-fluorophenyl)ethyl)-4-(2-((3S,4S)-3-fluorotetrahydro-2H-pyran-4-ylamino)pyrimidin-4-yl)pyridin-2(1H)-one.¹H NMR (400 MHz, CDCl₃) δ 8.39 (d, J=5.0 Hz, 1H), 7.40 (m, 2H),7.21-7.09 (m, 3H), 6.91 (d, J=5.2 Hz, 1H), 6.79 (m, 1H), 6.19 (m, 1H),5.34 (d, J=7.8 Hz, 1H), 4.61-4.42 (m, 1H), 4.38-4.26 (m, 3H), 4.10 (m,1H), 3.90 (m, 1H), 3.61-3.51 (m, 2H), 3.05 (br, s, 1H), 2.33 (m, 1H),1.63 (m, 1H); m/z (APCI-pos) M+1=463.1, 465.1.

Example 4

1-((S)-1-(3,4-dichlorophenyl)-2-hydroxyethyl)-4-(2-(((3S,4S)-3-fluorotetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one

Step A:1-((S)-2-(tert-Butyldimethylsilyloxy)-1-(3,4-dichlorophenyl)ethyl)-4-(2-((3S,4S)-3-fluorotetrahydro-2H-pyran-4-ylamino)pyrimidin-4-yl)pyridin-2(1H)-onewas prepared according to the general procedure of Example 2, Step A,substituting(S)-1-(2-(tert-butyldimethylsilyloxy)-1-(3,4-dichlorophenyl)ethyl)-4-(2-(methylsulfonyl)pyrimidin-4-yl)pyridin-2(1H)-onefor(S)-1-(2-(tert-butyldimethylsilyloxy)-1-(4-chloro-3-fluorophenyl)ethyl)-4-(2-(methylsulfonyl)pyrimidin-4-yl)pyridin-2(1H)-one.m/z (APCI-pos) M+1=593.1, 595.2.

Step B:1-((S)-1-(3,4-Dichlorophenyl)-2-hydroxyethyl)-4-(2-(((3S,4S)-3-fluorotetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one(74%, 2 steps; 98% e.e. by chiral HPLC (Chiral Tech, column OD-H, 4.6mm×250 mm, 5 u, 30% ethanol/70% hexanes, 1 mL/minute)) was preparedaccording to the general procedure of Example 2, Step B, substituting1-((S)-2-(tert-butyldimethylsilyloxy)-1-(3,4-dichlorophenyl)ethyl)-4-(2-((3S,4S)-3-fluorotetrahydro-2H-pyran-4-ylamino)pyrimidin-4-yl)pyridin-2(1H)-onefor1-((S)-2-(tert-butyldimethylsilyloxy)-1-(4-chloro-3-fluorophenyl)ethyl)-4-(2-(((3S,4S)-3-fluorotetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one.¹H NMR (400 MHz, CDCl₃) δ 8.39 (d, J=5.4 Hz, 1H), 7.50-7.38 (m, 3H),7.24-7.15 (m, 2H), 6.91 (d, J=5.2 Hz, 1H), 6.77 (m, 1H), 6.19 (m, 1H),5.53 (d, J=8.6 Hz, 1H), 4.75 (d, J=49 Hz, 1H), 4.40-4.18 (m, 4H), 4.10(m, 1H), 3.70-3.54 (m, 2H), 2.65 (br, s, 1H), 2.08-01.88 (m, 2H); m/z(APCI-pos) M+1=479.0, 481.0.

Example 5

1-((S)-1-(3,4-dichlorophenyl)-2-hydroxyethyl)-4-(2-(((3S,4R)-3-fluorotetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one

Step A:1-((S)-2-(tert-Butyldimethylsilyloxy)-1-(3,4-dichlorophenyl)ethyl)-4-(2-((3S,4R)-3-fluorotetrahydro-2H-pyran-4-ylamino)pyrimidin-4-yl)pyridin-2(1H)-onewas prepared according to the general procedure of Example 2, Step A,substituting (3S,4R)-3-fluorotetrahydro-2H-pyran-4-amine fortetrahydro-2H-pyran-4-amine and(S)-1-(2-(tert-butyldimethylsilyloxy)-1-(3,4-dichlorophenyl)ethyl)-4-(2-(methylsulfonyl)pyrimidin-4-yl)pyridin-2(1H)-onefor (S)-1-(2-(tert-butyldimethylsilyloxy)-1-(4-chloro-3-fluorophenyl)ethyl)-4-(2-(methylsulfonyl)pyrimidin-4-yl)pyridin-2(111H)-one. m/z(APCI-pos) M+1=593.1, 595.2.

Step B:1-((S)-1-(3,4-Dichlorophenyl)-2-hydroxyethyl)-4-(2-(((3S,4R)-3-fluorotetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one(54%, 2 steps; 98% e.e. by chiral HPLC (Chiral Tech, column OD-H, 4.6mm×250 mm, 5 u, 30% ethanol/70% hexanes, 1 mL/minute)) was preparedaccording to the general procedure of Example 2, Step B, substituting1-((S)-2-(tert-butyldimethylsilyloxy)-1-(3,4-dichlorophenyl)ethyl)-4-(2-((3S,4R)-3-fluorotetrahydro-2H-pyran-4-ylamino)pyrimidin-4-yl)pyridin-2(1H)-onefor1-((S)-2-(tert-butyldimethylsilyloxy)-1-(4-chloro-3-fluorophenyl)ethyl)-4-(2-((3S,4S)-3-fluorotetrahydro-2H-pyran-4-ylamino)pyrimidin-4-yl)pyridin-2(1H)-one.¹H NMR (400 MHz, CDCl₃) δ 8.39 (d, J=5.0 Hz, 1H), 7.49-7.45 (m, 2H),7.39 (d, J=7.4 Hz, 1H), 7.23-7.17 (m, 2H), 6.93 (d, J=5.2 Hz, 1H), 6.79(m, 1H), 6.19 (m, 1H), 5.31 (d, J=7.5 Hz, 1H), 4.61-4.42 (m, 1H),4.38-4.26 (m, 3H), 4.10 (m, 1H), 3.90 (m, 1H), 3.65-3.51 (m, 2H), 2.68r,s, 1H), 2.33 (m, 1H), 1.66 (m, 1H); m/z (APCI-pos) M+1=479.0, 481.0.

Example 6

1-((S)-1-(3-chloro-4-fluorophenyl)-2-hydroxyethyl)-4-(2-(((3S,4S)-3-fluorotetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one

Step A:1-((S)-2-(tert-Butyldimethylsilyloxy)-1-(3-chloro-4-fluorophenyl)ethyl)-4-(2-((3S,4S)-3-fluorotetrahydro-2H-pyran-4-ylamino)pyrimidin-4-yl)pyridin-2(1H)-onewas prepared according to the general procedure of Example 2, Step A,substituting(S)-1-(2-(tert-butyldimethylsilyloxy)-1-(3-chloro-4-fluorophenyl)ethyl)-4-(2-(methylsulfonyl)pyrimidin-4-yl)pyridin-2(1H)-onefor(S)-1-(2-(tert-butyldimethylsilyloxy)-1-(4-chloro-3-fluorophenyl)ethyl)-4-(2-(methylsulfonyl)pyrimidin-4-yl)pyridin-2(1H)-one.m/z (APCI-pos) M+1=577.2, 579.2.

Step B:1-((S)-1-(3-Chloro-4-fluorophenyl)-2-hydroxyethyl)-4-(2-(((3S,4S)-3-fluorotetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one(66%, 2 steps; 99% e.e. by chiral HPLC (Chiral Tech, column OD-H, 4.6mm×250 mm, 5 u, 20% ethanol/80% hexanes, 1 mL/minute)) was preparedaccording to the general procedure of Example 2, Step B, substituting1-((S)-2-(tert-butyldimethylsilyloxy)-1-(3-chloro-4-fluorophenyl)ethyl)-4-(2-((3S,4S)-3-fluorotetrahydro-2H-pyran-4-ylamino)pyrimidin-4-yl)pyridin-2(1H)-onefor1-((S)-2-(tert-butyldimethylsilyloxy)-1-(4-chloro-3-fluorophenyl)ethyl)-4-(2-(((3S,4S)-3-fluorotetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one.¹H NMR (400 MHz, CDCl₃) δ 8.38 (d, J=5.0 Hz, 1H), 7.46 (d, J=7.0 Hz,1H), 7.38 (d, J=7.8 Hz, 1H), 7.25 (m, 1H), 7.19-7.14 (m, 2H), 6.92 (d,J=5.0 Hz, 1H), 6.76 (d, J=6.6 Hz, 1H), 6.20 (m, 1H), 5.55 (d, J=9.4 Hz,1H), 4.75 (d, J=50 Hz, 1H), 4.38-4.18 (m, 4H), 4.08 (m, 1H), 3.69-3.53(m, 2H), 2.68 (br, s, 1H), 2.08-1.87 (m, 2H); m/z (APCI-pos) M+1=463.1,465.1.

Example 7

1-((S)-1-(3-chloro-4-fluorophenyl)-2-hydroxyethyl)-4-(2-(((3S,4R)-3-fluorotetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one

Step A:1-((S)-2-(tert-Butyldimethylsilyloxy)-1-(3-chloro-4-fluorophenyl)ethyl)-4-(2-((3S,4R)-3-fluorotetrahydro-2H-pyran-4-ylamino)pyrimidin-4-yl)pyridin-2(1H)-onewas prepared according to the general procedure of Example 2, Step A,substituting (3S,4R)-3-fluorotetrahydro-2H-pyran-4-amine fortetrahydro-2H-pyran-4-amine and(S)-1-(2-(tert-butyldimethylsilyloxy)-1-(3-chloro-4-fluorophenyl)ethyl)-4-(2-(methylsulfonyl)pyrimidin-4-yl)pyridin-2(1H)-onefor(S)-1-(2-(tert-butyldimethylsilyloxy)-1-(4-chloro-3-fluorophenyl)ethyl)-4-(2-(methylsulfonyl)pyrimidin-4-yl)pyridin-2(1H)-one.m/z (APCI-pos) M+1=577.2, 579.2.

Step B:1-((S)-1-(3-Chloro-4-fluorophenyl)-2-hydroxyethyl)-4-(2-(((3S,4R)-3-fluorotetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one(59%, 2 steps; 99% e.e. by chiral HPLC (Chiral Tech, column OJ-H, 4.6mm×250 mm, 5 u, 20% ethanol/80% hexanes, 1 mL/minute)) was preparedaccording to the general procedure of Example 2, Step B, substituting1-((S)-2-(tert-butyldimethylsilyloxy)-1-(3-chloro-4-fluorophenyl)ethyl)-4-(2-((3S,4R)-3-fluorotetrahydro-2H-pyran-4-ylamino)pyrimidin-4-yl)pyridin-2(1H)-onefor1-((S)-2-(tert-butyldimethylsilyloxy)-1-(4-chloro-3-fluorophenyl)ethyl)-4-(2-(((3S,4S)-3-fluorotetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one.¹H NMR (400 MHz, CDCl₃) δ 8.38 (d, J=5.0 Hz, 1H), 7.46 (d, J=7.0 Hz,1H), 7.38 (d, J=7.8 Hz, 1H), 7.25 (m, 1H), 7.19-7.14 (m, 2H), 6.92 (d,J=5.0 Hz, 1H), 6.76 (d, J=6.6 Hz, 1H), 6.20 (m, 1H), 5.34 (d, J=7.8 Hz,1H), 4.61-4.42 (m, 1H), 4.38-4.26 (m, 3H), 4.10 (m, 1H), 3.90 (m, 1H),3.61-3.51 (m, 2H), 3.05 (br, s, 1H), 2.33 (m, 1H), 1.63 (m, 1H); m/z(APCI-pos) M+1=463.1, 465.1.

Example 8

1-((S)-1-(3,4-dichlorophenyl)-2-hydroxyethyl)-4-(2-(((1S,3S)-3-hydroxycyclopentyl)amino)pyrimidin-4-yl)pyridin-2(1H)-one

Step A:1-((S)-2-(tert-Butyldimethylsilyloxy)-1-(3,4-dichlorophenyl)ethyl)-4-(2-((1S,3S)-3-hydroxycyclopentylamino)pyrimidin-4-yl)pyridin-2(1H)-onewas prepared according to the general procedure of Example 2, Step A,substituting (1S,3S)-3-aminocyclopentanol fortetrahydro-2H-pyran-4-amine and(S)-1-(2-(tert-butyldimethylsilyloxy)-1-(3,4-dichlorophenyl)ethyl)-4-(2-(methylsulfonyl)pyrimidin-4-yl)pyridin-2(1H)-onefor(S)-1-(2-(tert-butyldimethylsilyloxy)-1-(4-chloro-3-fluorophenyl)ethyl)-4-(2-(methylsulfonyl)pyrimidin-4-yl)pyridin-2(1H)-one.m/z (APCI-pos) M+1=575.2, 577.1.

Step B:1-((S)-1-(3,4-Dichlorophenyl)-2-hydroxyethyl)-4-(2-(((1S,3S)-3-hydroxycyclopentyl)amino)pyrimidin-4-yl)pyridin-2(1H)-one(78%, 2 steps; 97% e.e. by chiral HPLC (Chiral Tech, column OD-H, 4.6mm×250 mm, 5 u, 30% ethanol/70% hexanes, 1 mL/minute)) was preparedaccording to the general procedure of Example 1, Step B, substituting1-((S)-2-(tert-butyldimethylsilyloxy)-1-(3,4-dichlorophenyl)ethyl)-4-(2-((1S,3S)-3-hydroxycyclopentylamino)pyrimidin-4-yl)pyridin-2(1H)-onefor(S)-1-(2-(tert-butyldimethylsilyloxy)-1-(4-chloro-3-fluorophenyl)ethyl)-4-(2-(tetrahydro-2H-pyran-4-ylamino)pyrimidin-4-yl)pyridin-2(1H)-one.¹H NMR (400 MHz, CDCl₃) δ 8.31 (d, J=4.2 Hz, 1H), 7.48 (s, 1H), 7.44 (d,J=8.0 Hz, 1H), 7.39 (d, J=7.2 Hz, 1H), 7.21 (m, 1H), 7.13 (s, 1H), 6.80(m, 2H), 6.17 (m, 1H), 5.22 (d, J=7.2 Hz, 1H), 4.60-4.43 (m, 2H), 4.30(m, 2H), 3.50 (br, s, 2H), 2.36 (m, 1H), 2.22 (m, 1H), 2.11 (m, 1H),1.77-1.64 (m, 2H), 1.52 (m, 1H); m/z (APCI-pos) M+1=461.0, 463.1.

Example 9

(S)-1-(1-(4-chloro-3-fluorophenyl)-2-hydroxyethyl)-4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one

A solution of 1-methyl-1H-pyrazol-4-amine (0.054 g, 0.56 mmol) and(S)-1-(2-(tert-butyldimethylsilyloxy)-1-(4-chloro-3-fluorophenyl)ethyl)-4-(2-(methylsulfonyl)pyrimidin-4-yl)pyridin-2(1H)-one(0.060 g, 0.11 mmol) in sec-BuOH (1 mL) was heated to 120° C. in amicrowave reactor for 2 hours. The reaction mixture was cooled to roomtemperature and concentrated. The residue was diluted with ethyl acetateand washed with H₂O (2×). The organic layer was dried, filtered andconcentrated. The crude product was purified by column chromatography,eluting with DCM/MeOH (25:1) to give(S)-1-(1-(4-chloro-3-fluorophenyl)-2-hydroxyethyl)-4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one(0.013 g, 26%). ¹H NMR (400 MHz, CD₃OD) δ 8.50 (d, J=5.0 Hz, 1H), 7.96(s, 1H), 7.85 (d, J=7.0 Hz, 1H), 7.58 (s, 1H), 7.48 (m, 1H), 7.34-7.28(m, 2H), 7.20-7.17 (m, 2H), 7.06 (m, 1H), 6.12 (m, 1H), 4.28 (m, 1H),4.19 (m, 1H), 3.88 (s, 3H); m/z (APCI-pos) M+1=441.1, 443.1.

Example 10

1-((S)-(4-chloro-3-fluorophenyl)((R)-pyrrolidin-2-yl)methyl)-4-(2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one

Step A: (R)-1-(tert-Butoxycarbonyl)pyrrolidine-2-carboxylic acid (5.00g, 23.2 mmol), O,N-dimethylhydroxylamine hydrochloride (2.49 g, 25.6mmol), diisopropyl ethyl amine (8.09 mL, 46.5 mmol) and2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyl uroniumhexafluorophosphate methanaminium (“HATU”) (9.72 g, 25.6 mmol) in DCM(50 mL) were stirred at room temperature for 2 hours. The reactionmixture was quenched with water, and the layers were separated. Theaqueous layer was extracted with DCM (1×), and the combined organicswere dried, filtered and concentrated. The crude product was purifiedvia column chromatography, eluting with hexanes/ethyl acetate (1:1) togive (R)-tert-butyl2-(methoxy(methyl)carbamoyl)pyrrolidine-1-carboxylate as an oil (5.5 g,92%). m/z (APCI-pos) (M+1)-Boc=159.0.

Step B: 0.5M (4-Chloro-3-fluorophenyl)magnesium bromide (22.5 mL, 11.2mmol) as a solution in THF was added dropwise to a cold (0° C.) solutionof (R)-tert-butyl 2-(methoxy(methyl)carbamoyl)pyrrolidine-1-carboxylate(1.45 g, 5.61 mmol) in THF (25 mL) under N₂, and the reaction wasallowed to warm up to room temperature overnight. The next morning, themixture was placed in an ice bath and carefully quenched with ice. Thereaction mixture was concentrated. The residue was treated for 1 hourwith a solution of 30% sodium potassium and then extracted with ethylacetate (2×). The organic layer was dried, filtered and concentrated.The crude product was purified via column chromatography, eluting withhexanes/ethyl acetate (5:1) to give (R)-tert-butyl2-(4-chloro-3-fluorobenzoyl)pyrrolidine-1-carboxylate (1.12 g, 61%). m/z(APCI-pos) (M+1)-Boc=228.1, 230.1.

Step C: (R)-tert-Butyl2-(4-chloro-3-fluorobenzoyl)pyrrolidine-1-carboxylate (1.12 g, 3.42mmol) was placed in THF (50 mL) at −78° C., and 1.0M L-Selectride® (5.13mL, 5.13 mmol) as a solution in THF was added. The reaction was stirredat −78° C. for 1 hour and then 0° C. for 2 hours. The reaction wasquenched with 1N HCl, and the pH was adjusted to about 7 with saturatedNaHCO₃. The mixture was concentrated to remove most of the THF, and theresidue was extracted with ethyl acetate (2×). The combined organicswere dried, filtered and concentrated. The crude product was purifiedvia column chromatography, eluting with hexanes/ethyl acetate (12:1) togive (R)-tert-butyl2-((R)-(4-chloro-3-fluorophenyl)(hydroxy)methyl)pyrrolidine-1-carboxylate(0.67 g, 60%). m/z (APCI-pos) (M+1)-Boc=230.1, 232.1.

Step D: A solution of (R)-tert-butyl2-((R)-(4-chloro-3-fluorophenyl)(hydroxy)methyl)pyrrolidine-1-carboxylate(0.662 g, 2.01 mmol) and triphenylphosphine (0.658 g, 2.51 mmol) in THF(40 mL) was placed in an ice bath, and diisopropyl azodicarboxylate(0.518 mL, 2.51 mmol) was added. The cold bath was removed after 10minutes, and the reaction mixture was stirred at room temperature for 10minutes. 4-(2-(Methylthio)pyrimidin-4-yl)pyridin-2(1H)-one (0.22 g, 1.00mmol) was added, and the reaction was left at room temperature for 1hour. The reaction mixture was concentrated, and the crude product waspurified via column chromatography, eluting with hexanes/ethyl acetate(1:1) to give (R)-tert-butyl2-((S)-(4-chloro-3-fluorophenyl)(4-(2-(methylthio)pyrimidin-4-yl)-2-oxopyridin-1(2H)-yl)methyl)pyrrolidine-1-carboxylate(contaminated with large amounts of PPh₃O). m/z (APCI-pos)(M+1)-Boc=431.2, 433.2.

Step E: (R)-tert-Butyl2-((S)-(4-chloro-3-fluorophenyl)(4-(2-(methylsulfonyl)pyrimidin-4-yl)-2-oxopyridin-1(2H)-yl)methyl)pyrrolidine-1-carboxylate(33%, 2 steps) was prepared according to the general procedure ofIntermediate Example C, Step B, substituting (R)-tert-butyl2-((S)-(4-chloro-3-fluorophenyl)(4-(2-(methylthio)pyrimidin-4-yl)-2-oxopyridin-1(2H)-yl)methyl)pyrrolidine-1-carboxylatefor(S)-1-(2-(tert-butyldimethylsilyloxy)-1-(4-chloro-3-fluorophenyl)ethyl)-4-(2-(methylthio)pyrimidin-4-yl)pyridin-2(1H)-one.m/z (APCI-pos) (M+1)-Boc=463.0, 465.0.

Step F: (R)-tert-Butyl2-((S)-(4-chloro-3-fluorophenyl)(2-oxo-4-(2-(tetrahydro-2H-pyran-4-ylamino)pyrimidin-4-yl)pyridin-1(2H)-yl)methyl)pyrrolidine-1-carboxylate was prepared according to thegeneral procedure of Example 1, Step A, substituting (R)-tert-butyl2-((S)-(4-chloro-3-fluorophenyl)(4-(2-(methylsulfonyl)pyrimidin-4-yl)-2-oxopyridin-1(2H)-yl)methyl)pyrrolidine-1-carboxylatefor(S)-1-(2-(tert-butyldimethylsilyloxy)-1-(4-chloro-3-fluorophenyl)ethyl)-4-(2-(methylsulfonyl)pyrimidin-4-yl)pyridin-2(1H)-one.m/z (APCI-pos) (M+1)-Boc=484.1, 486.1.

Step G:1-((S)-(4-Chloro-3-fluorophenyl)((R)-pyrrolidin-2-yl)methyl)-4-(2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one(74%, 2 steps) was prepared according to the general procedure ofExample 2, Step B, substituting (R)-tert-butyl2-((S)-(4-chloro-3-fluorophenyl)(2-oxo-4-(2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)pyridin-1(2H)-yl)methyl)pyrrolidine-1-carboxylate for1-((S)-2-(tert-butyldimethylsilyloxy)-1-(4-chloro-3-fluorophenyl)ethyl)-4-(2-(((3S,4S)-3-fluorotetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one.¹H NMR (400 MHz, CDCl₃) δ 8.37 (d, J=5.0 Hz, 1H), 7.52 (d, J=7.0 Hz,1H), 7.41-7.36 (m, 2H), 7.30 (m, 1H), 7.15 (s, 1H), 6.87 (d, J=5.2 Hz,1H), 6.75 (m, 1H), 6.03 (d, J=9.0 Hz, 1H), 5.13 (d, J=7.6 Hz, 1H), 4.10(m, 1H), 4.01 (m, 2H), 3.92 (m, 1H), 3.55 (m, 2H), 3.00 (m, 2H), 2.07(m, 2H), 1.87 (m, 2H), 1.73 (m, 1H), 1.60 (m, 4H); m/z (APCI-pos)M+1=484.1, 486.1.

Example 11

(S)-2-(1-(4-chloro-3-fluorophenyl)-2-hydroxyethyl)-5-(2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)pyridazin-3(2H)-one

Step A: 1.0M KOt-Bu (2.64 mL, 2.64 mmol) in THF and tetrabutylammoniumiodide (0.0749 g, 0.203 mmol) were added to a solution of5-iodopyridazin-3(2H)-one (0.45 g, 2.03 mmol) in THF (10 mL). Themixture was stirred at room temperature for 10 minutes before(R)-2-(tert-butyldimethylsilyloxy)-1-(4-chloro-3-fluorophenyl)ethylmethanesulfonate (1.16 g, 3.04 mmol) was added as a solution in THF (10mL). The reaction was heated to reflux for 90 hours, then cooled to roomtemperature and concentrated. The residue was taken up in ethyl acetateand washed with water (2×). The organics were dried, filtered andconcentrated. The crude product was purified via column chromatography,eluting with hexanes/ethyl acetate (25:1) to give(S)-2-(2-(tert-butyldimethylsilyloxy)-1-(4-chloro-3-fluorophenyl)ethyl)-5-iodopyridazin-3(2H)-one(0.65 g, 63%). ¹H NMR (400 MHz, CDCl₃) δ 7.98 (d, J=2.0 Hz, 1H), 7.45(d, J=2.2 Hz, 1H), 7.35 (m, 1H), 7.23 (m, 1H), 7.16 (m, 1H), 6.09 (m,1H), 4.34 (m, 1H), 4.01 (m, 1H), 0.81 (s, 9H), 0.01 (s, 3H), −0.01 (s,3H).

Step B: A solution of(S)-2-(2-(tert-butyldimethylsilyloxy)-1-(4-chloro-3-fluorophenyl)ethyl)-5-iodopyridazin-3(2H)-one(0.402 g, 0.790 mmol), 2-(methylthio)-4-(tributylstannyl)pyrimidine(0.361 g, 0.869 mmol), copper(I) iodide (0.0150 g, 0.0790 mmol) andPdCl₂(PPh₃)₂(0.0555 g, 0.0790 mmol) in NMP (4 mL) was heated to 120° C.under Ar for 16 hours. The reaction mixture was cooled to roomtemperature and diluted with ethyl acetate (200 mL). The organics werewashed with brine (3×50 mL), dried, filtered and concentrated. The crudeproduct was purified via column chromatography, eluting withhexanes/ethyl acetate (1:1) to give(S)-2-(1-(4-chloro-3-fluorophenyl)-2-hydroxyethyl)-5-(2-(methylthio)pyrimidin-4-yl)pyridazin-3(2H)-one(0.25 g, 79%). m/z (APCI-pos) M+1=393.0, 395.0.

Step C:(S)-2-(1-(4-Chloro-3-fluorophenyl)-2-hydroxyethyl)-5-(2-(methylsulfonyl)pyrimidin-4-yl)pyridazin-3(2H)-one(58%) was prepared according to the general procedure of IntermediateExample C, Step B, substituting(S)-2-(1-(4-chloro-3-fluorophenyl)-2-hydroxyethyl)-5-(2-(methylthio)pyrimidin-4-yl)pyridazin-3(2H)-onefor(S)-1-(2-(tert-butyldimethylsilyloxy)-1-(4-chloro-3-fluorophenyl)ethyl)-4-(2-(methylthio)pyrimidin-4-yl)pyridin-2(1H)-one.m/z (APCI-pos) M+1=425.0, 427.0.

Step D:(S)-2-(1-(4-Chloro-3-fluorophenyl)-2-hydroxyethyl)-5-(2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)pyridazin-3(2H)-one(78%) was prepared according to the general procedure of Example 1, StepA, substituting(S)-2-(1-(4-chloro-3-fluorophenyl)-2-hydroxyethyl)-5-(2-(methylsulfonyl)pyrimidin-4-yl)pyridazin-3(2H)-one for(S)-1-(2-(tert-butyldimethylsilyloxy)-1-(4-chloro-3-fluorophenyl)ethyl)-4-(2-(methylsulfonyl)pyrimidin-4-yl)pyridin-2(1H)-one.¹H NMR (400 MHz, CD₃OD) δ 8.68 (d, J=2.2 Hz, 1H), 8.41 (d, J=5.2 Hz,1H), 7.56 (d, J=2.2 Hz, 1H), 7.45 (m, 1H), 7.34 (m, 1H), 7.24 (m, 1H),7.15 (d, J=5.4 Hz, 1H), 6.18 (m, 1H), 4.42 (m, 1H), 4.06-3.97 (m, 4H),3.56 (m, 2H), 2.00 (m, 2H), 1.62 (m, 2H); m/z (APCI-pos) M+1=446.1,448.1.

Example 12

1-(1-(4-chloro-3-fluorophenyl)-2-hydroxyethyl)-4-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one

Step A: Sodium carbonate (0.575 g, 5.43 mmol) was added to2-fluoropyridin-4-ylboronic acid (0.306 g, 2.17 mmol) and2,4-dichloro-5-methylpyrimidine (0.212 mL, 1.81 mmol) in dioxane/water(10 mL; 4:1), and the suspension was purged with nitrogen.PdCl₂(dppf)*DCM (0.0739 g, 0.0905 mmol) was added, and the vial wassealed and heated at 80° C. After 3 hours, the cooled reaction mixturewas partitioned between water and EtOAc. The EtOAc was washed withbrine, dried over MgSO₄, filtered, and evaporated to yield a crudeproduct (0.50 g) as a solid. The crude product was absorbed on silicagel and chromatographed on a 50 g Biotage SNAP column with 1:1hexane/EtOAc. Fractions 16-34 contained2-chloro-4-(2-fluoropyridin-4-yl)-5-methylpyrimidine (0.22 g, 0.984mmol, 54.4% yield) with minor impurities.

Step B: Tetrahydro-2H-pyran-4-amine (0.109 g, 1.08 mmol) andN-ethyl-N-isopropylpropan-2-amine (0.258 mL, 1.48 mmol) were added to2-chloro-4-(2-fluoropyridin-4-yl)-5-methylpyrimidine (0.22 g, 0.984mmol) in DMA (2 mL). The mixture was heated in a microwave at 180° C.for 30 minutes. The reaction mixture was partitioned between water andEtOAc. The EtOAc was washed with water, brine, dried over MgSO₄,filtered, and evaporated to yield a crude product (0.28 g) as a film.The crude product was chromatographed on a 50 g Biotage SNAP column withEtOAc. Fractions 17-32 contained4-(2-fluoropyridin-4-yl)-5-methyl-N-(tetrahydro-2H-pyran-4-yl)pyrimidin-2-amine(0.158 g, 0.548 mmol, 55.7% yield) as a solid.

Step C: 1M HCl (10 mL) was added to4-(2-fluoropyridin-4-yl)-5-methyl-N-(tetrahydro-2H-pyran-4-yl)pyrimidin-2-amine(0.158 g, 0.548 mmol). The mixture was heated at reflux. After 2 hours,the cooled reaction mixture was neutralized with solid NaHCO₃. Theresulting solid was collected by vacuum filtration and dried to afford4-(5-methyl-2-(tetrahydro-2H-pyran-4-ylamino)pyrimidin-4-yl)pyridin-2(1H)-one(0.126 g, 0.440 mmol, 80.3% yield) as a solid.

Step D: 0.55 g PS-triphenylphosphine 1.99 mmol/g (0.289 g, 1.10 mmol)was added to2-(tert-butyldimethylsilyloxy)-1-(4-chloro-3-fluorophenyl)ethanol (0.268g, 0.880 mmol) in DCM (15 mL) cooled in ice. (E)-Diisopropyldiazene-1,2-dicarboxylate (0.216 mL, 1.10 mmol) was added dropwise tothe mixture. After 10 minutes allowing the reaction mixture to warm toambient temperature, a suspension of4-(5-methyl-2-(tetrahydro-2H-pyran-4-ylamino)pyrimidin-4-yl)pyridin-2(1H)-one(0.126 g, 0.440 mmol) in DCM (5 mL) was added. The mixture was stirredat ambient temperature. After 4 hours, an additional 1 equivalent DIADwas added, and the mixture stirred overnight. The reaction mixture wasfiltered and evaporated. The residue was partitioned between water andEtOAc. The EtOAc was washed with brine, dried over MgSO₄, filtered, andevaporated to yield a crude product (0.64 g) as an oil. The crudeproduct was chromatographed on a 50 g Biotage SNAP column with 2:1EtOAc/hexane. Fractions 60-84 contained1-(2-(tert-butyldimethylsilyloxy)-1-(4-chloro-3-fluorophenyl)ethyl)-4-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one(0.033 g, 0.0576 mmol, 13.1% yield) as a glass.

Step E: 1M Tetrabutylammonium fluoride in THF (0.173 mL, 0.173 mmol) wasadded to1-(2-(tert-butyldimethylsilyloxy)-1-(4-chloro-3-fluorophenyl)ethyl)-4-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one(0.033 g, 0.0576 mmol) in THF (3 mL). The mixture was stirred at ambienttemperature. After 1 hour, the reaction mixture was evaporated, and theresidue was partitioned between water and EtOAc. The EtOAc was washedwith brine, dried over MgSO₄, filtered, and evaporated to yield a crudeproduct (0.0394 g) as a solid. The crude product was purified bychromatography on a 10 g Biotage SNAP column with 10:1 EtOAc/MeOH.Fractions 7-12 contained1-(1-(4-chloro-3-fluorophenyl)-2-hydroxyethyl)-4-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one(0.0206 g, 0.0449 mmol, 78.0% yield) as a glass. ¹H NMR (400 MHz, CD₃OD)δ 8.21 (s, 1H), 7.82 (d, 1H), 7.50-7.46 (m, 1H), 7.35-7.31 (m, 1H),7.21-7.18 (m, 1H), 6.72 (d, 1H), 6.59 (dd, 1H), 4.32-4.26 (m, 1H),4.22-4.17 (m, 1H), 4.12-4.07 (m, 1H), 4.00-3.92 (m, 2H), 3.54-3.47 (m,2H), 2.17 (s, 3H), 1.99-1.93 (m, 2H), 1.62-1.52 (m, 2H); m/z (APCI-pos)M+1=459.1.

Example 13

1-(1-(3-chlorophenyl)-2-hydroxyethyl)-4-(5-fluoro-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one

Step A: Triphenylphosphine (0.565 g, 2.15 mmol) was added to2-(tert-butyldimethylsilyloxy)-1-(3-chlorophenyl)ethanol (0.494 g, 1.72mmol; prepared as Intermediate Example I, Steps A and B, substituting(3-chlorophenyl)magnesium bromide for (4-chloro-3-fluorophenyl)magnesiumbromide in Step A) in DCM (20 mL) cooled in ice. (E)-Diisopropyldiazene-1,2-dicarboxylate (0.423 mL, 2.15 mmol) was added dropwise tothe mixture. After 10 minutes allowing the reaction mixture to warm toroom temperature, the solution was added to4-(5-fluoro-2-(tetrahydro-2H-pyran-4-ylamino)pyrimidin-4-yl)pyridin-2(1H)-one(0.25 g, 0.861 mmol), washing in with DCM (10 mL). The suspension wasstirred at ambient temperature overnight. The reaction mixture wasfiltered, and the filtrate was evaporated to provide a crude product.The crude product was chromatographed on a 50 g Biotage SNAP column with2:1 EtOAc/hexane. Fractions 20-36 contained1-(2-(tert-butyldimethylsilyloxy)-1-(3-chlorophenyl)ethyl)-4-(5-fluoro-2-(tetrahydro-2H-pyran-4-ylamino)pyrimidin-4-yl)pyridin-2(1H)-one(0.0307 g, 0.0549 mmol, 6.38% yield) as a film.

Step B: 1M Tetrabutylammonium fluoride in THF (0.165 mL, 0.165 mmol) wasadded to1-(2-(tert-butyldimethylsilyloxy)-1-(3-chlorophenyl)ethyl)-4-(5-fluoro-2-(tetrahydro-2H-pyran-4-ylamino)pyrimidin-4-yl)pyridin-2(1H)-one(0.0307 g, 0.0549 mmol) in THF (3 mL). The mixture was stirred at roomtemperature for 30 minutes. The reaction mixture was evaporated, and theresidue was partitioned between water and EtOAc. The EtOAc was washedwith brine, dried over MgSO₄, filtered, and evaporated to yield a crudeproduct as a film. The crude product was purified by chromatography on a10 g Biotage SNAP column with EtOAc. Fractions 17-32 contained a glass(16.2 mg). The glass was triturated with water and dried to afford1-(1-(3-chlorophenyl)-2-hydroxyethyl)-4-(5-fluoro-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one(0.0129 g, 0.0290 mmol, 52.8% yield) as a film. ¹H NMR (400 MHz, CD₃OD)δ 8.33 (d, 1H), 7.84 (d, 1H), 7.43-7.24 (m, 5H), 7.03-6.99 (m, 1H),6.16-6.12 (m, 1H), 4.32-4.27 (m, 1H), 4.22-4.17 (m, 1H), 4.02-3.94 (m,3H), 3.57-3.49 (m, 2H), 2.02-1.96 (m, 2H), 1.64-1.54 (m, 2H); m/z(APCI-pos) M+1=445.1.

Example 14

1-(1-(4-chloro-3-fluorophenyl)-2-hydroxyethyl)-4-(2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)pyrimidin-2(1H)-one

Step A: 1,1-Dimethoxy-N,N-dimethylmethanamine (9.87 mL, 74.3 mmol) wasadded to 1-(2-(methylthio)pyrimidin-4-yl)ethanone (0.50 g, 2.97 mmol).The mixture was heated at reflux overnight. The reaction mixture wasconcentrated to half volume and treated with Et₂O. The resulting solidwas collected by vacuum filtration to yield the desired(E)-3-(dimethylamino)-1-(2-(methylthio)pyrimidin-4-yl)prop-2-en-1-one(0.46 g, 2.06 mmol, 69.3% yield).

Step B: A well-stirred solid mixture of(E)-3-(dimethylamino)-1-(2-(methylthio)pyrimidin-4-yl)prop-2-en-1-one(0.206 g, 0.923 mmol), urea (1.11 g, 18.5 mmol), and 60% sodium hydride(0.0922 g, 2.31 mmol) was heated in a sand bath preheated to 140° C. for3 minutes until complete melting and then 2 additional minutes as amelt. The cooled reaction mixture was treated with water. The solutionwas acidified to pH 3 with 1M HCl, and the resulting solid was collectedby vacuum filtration to yield a crude product (0.082 g). The crude waschromatographed on a 50 g Biotage SNAP column with 10:1 DCM/MeOH.Fractions 16-48 contained the desired4-(2-(methylthio)pyrimidin-4-yl)pyrimidin-2(1H)-one (0.04 g, 0.182 mmol,19.7% yield) as a solid.

Step C: Potassium 2-methylpropan-2-olate (0.026 g, 0.24 mmol) andtetrabutylammonium iodide (0.0067 g, 0.018 mmol) were added to4-(2-(methylthio)pyrimidin-4-yl)pyrimidin-2(1H)-one (0.040 g, 0.18 mmol)suspended in THF (4 mL) cooled in ice. After 10 minutes, a solution of2-(tert-butyldimethylsilyloxy)-1-(4-chloro-3-fluorophenyl)ethylmethanesulfonate (0.10 g, 0.27 mmol) in THF (1 mL) was added. Themixture was stirred at room temperature overnight and then heated at 90°C. for 3 days. Due to incomplete reaction, the material was transferredto a microwave vial and heated in a microwave at 130° C. for 1 hour. Thereaction mixture was evaporated, and the residue was chromatographed ona 10 g Biotage SNAP column with 1:1 hexane/EtOAc. Fractions 8-13contained the desired1-(2-(tert-butyldimethylsilyloxy)-1-(4-chloro-3-fluorophenyl)ethyl)-4-(2-(methylthio)pyrimidin-4-yl)pyrimidin-2(1H)-one(0.030 g, 0.059 mmol, 33% yield) as a film.

Step D: 3-Chlorobenzoperoxoic acid (0.0306 g, 0.177 mmol) was added to1-(2-(tert-butyldimethylsilyloxy)-1-(4-chloro-3-fluorophenyl)ethyl)-4-(2-(methylthio)pyrimidin-4-yl)pyrimidin-2(1H)-one(0.030 g, 0.0592 mmol) in DCM (5 mL). The mixture was stirred at roomtemperature. After 2 hours, the reaction mixture was evaporated. Theresidue was taken up in EtOAc, washed twice with a mixture of saturatedaqueous Na₂S₂O₃ and saturated aqueous NaHCO₃, brine, dried over MgSO₄,filtered, and evaporated to yield1-(2-(tert-butyldimethylsilyloxy)-1-(4-chloro-3-fluorophenyl)ethyl)-4-(2-(methylsulfonyl)pyrimidin-4-yl)pyrimidin-2(1H)-one(0.0349 g, 0.0647 mmol, 109% yield).

Step E: Tetrahydro-2H-pyran-4-amine (0.0327 g, 0.324 mmol) was added to1-(2-(tert-butyldimethylsilyloxy)-1-(4-chloro-3-fluorophenyl)ethyl)-4-(2-(methylsulfonyl)pyrimidin-4-yl)pyrimidin-2(1H)-one(0.0349 g, 0.0647 mmol) in THF (5 mL). The mixture was heated in amicrowave at 120° C. for 1 hour and then at 130° C. for 1.5 hours. Thereaction mixture was evaporated, and the residue partitioned betweenEtOAc and water. The EtOAc was washed with brine, dried over MgSO₄,filtered, and evaporated to yield a crude product (30.2 mg) as a film.The crude product was chromatographed on a 10 g Biotage SNAP column with2:1 EtOAc/hexane. Fractions 23-34 contained the desired1-(2-(tert-butyldimethylsilyloxy)-1-(4-chloro-3-fluorophenyl)ethyl)-4-(2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)pyrimidin-2(1H)-one(0.0048 g, 0.00857 mmol, 13.2% yield) as a film.

Step F: 1M Tetrabutylammonium fluoride in THF (0.026 mL, 0.026 mmol) wasadded to1-(2-(tert-butyldimethylsilyloxy)-1-(4-chloro-3-fluorophenyl)ethyl)-4-(2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)pyrimidin-2(1H)-one(0.0048 g, 0.0086 mmol) in THF (2 mL). The mixture was stirred at roomtemperature for 1 hour. The reaction mixture was evaporated, and theresidue was partitioned between water and EtOAc. The EtOAc was washedwith brine, dried over MgSO₄, filtered, and evaporated to yield a crudeproduct (2.8 mg) as a film. The crude product was purified bychromatography on a preparative thin layer chromatography (“TLC”) plate,eluting with 10:1 DCM/MeOH. The major band contained the desired1-(1-(4-chloro-3-fluorophenyl)-2-hydroxyethyl)-4-(2-(tetrahydro-2H-pyran-4-ylamino)pyrimidin-4-yl)pyrimidin-2(1H)-one(0.0006 g, 0.0013 mmol, 16% yield). m/z (APCI-pos) M+1=446.1.

Example 15

1-benzhydryl-4-(2-((tetrahydro-2H-pyran-4-ylamino)pyrimidin-4-yl)pyridin-2(1H)-one

Step A: 60% Sodium hydride (0.036 g, 0.89 mmol) was added to asuspension of (bromomethylene)dibenzene (0.19 g, 0.75 mmol) and4-(2-(methylthio)pyrimidin-4-yl)pyridin-2(1H)-one (0.15 g, 0.68 mmol) inDMF (3 mL). The mixture was stirred at ambient temperature overnight.The mixture was then heated at 50° C. overnight. The reaction mixturewas diluted with dilute aqueous NaCl and extracted with EtOAc. The EtOAcwas washed with brine, dried over MgSO₄, filtered, and evaporated toyield a crude product (0.28 g) as a film. This was chromatographed on a10 g Biotage SNAP column with 1:1 EtOAc/hexane. Fractions 13-22contained the desired1-benzhydryl-4-(2-(methylthio)pyrimidin-4-yl)pyridin-2(1H)-one (0.11 g,0.29 mmol, 42% yield) as a solid foam.

Step B: 3-Chlorobenzoperoxoic acid (0.15 g, 0.86 mmol) was added to1-benzhydryl-4-(2-(methylthio)pyrimidin-4-yl)pyridin-2(1H)-one (0.11 g,0.29 mmol) in DCM (10 mL). The mixture was stirred at ambienttemperature. After 5 hours, the reaction mixture was evaporated. Theresidue was taken up in EtOAc, washed twice with a mixture of saturatedaqueous Na₂S₂O₃ and saturated aqueous NaHCO₃, brine, dried over MgSO₄,filtered, and evaporated to yield the desired1-benzhydryl-4-(2-(methylsulfonyl)pyrimidin-4-yl)pyridin-2(1H)-one (0.12g, 0.29 mmol, 101% yield) as a film.

Step C: Tetrahydro-2H-pyran-4-amine (0.20 g, 2.0 mmol) was added to1-benzhydryl-4-(2-(methylsulfonyl)pyrimidin-4-yl)pyridin-2(1H)-one (0.12g, 0.29 mmol) in DMA (3 mL) in a microwave vial. The mixture was heatedat 120° C. for 1 hour in a microwave. The reaction mixture was dilutedwith water and extracted with EtOAc. The EtOAc was washed with water,twice with brine, dried over MgSO₄, filtered, and evaporated to yield acrude product (0.09 g) as a film. This was chromatographed on a 10 gBiotage SNAP column with EtOAc. Fractions 9-20 contained a film (0.0764g). This was triturated with water, dried, then triturated with hexaneand dried to afford the desired1-benzhydryl-4-(2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one(0.072 g, 0.16 mmol, 57% yield) as a film. ¹H NMR (400 MHz, CDCl₃) δ8.38 (d, 1H), 7.52 (s, 1H), 7.40-7.15 (m, 9H), 6.91 (d, 1H), 6.76-6.72(m, 1H), 5.25-5.21 (m, 1H), 4.15-4.06 (m, 1H), 4.02-3.96 (m, 2H),3.59-3.51 (m, 2H), 2.09-2.03 (m, 2H), 1.62-1.52 (m, 2H); m/z (APCI-pos)M+1=439.2.

Example 16

(S)-1-(1-(4-chloro-3-fluorophenyl)-2-hydroxyethyl)-4-(5-fluoro-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one

Step A: 1.0M Potassium 2-methylpropan-2-olate in THF (0.49 mL, 0.49mmol) and tetrabutylammonium iodide (0.017 g, 0.045 mmol) were added to4-(5-fluoro-2-(tetrahydro-2H-pyran-4-ylamino)pyrimidin-4-yl)pyridin-2(1H)-one(0.13 g, 0.45 mmol) in THF (8 mL) cooled in ice. The mixture was stirred10 minutes. A solution of(R)-2-(tert-butyldimethylsilyloxy)-1-(4-chloro-3-fluorophenyl)ethylmethanesulfonate (0.31 g, 0.81 mmol) in THF (2 mL) was added, and themixture was heated at 60° C. in a sealed vial overnight. The reactionmixture was evaporated, and the residue was partitioned between waterand EtOAc. The EtOAc was washed with brine, dried over MgSO₄, filtered,and evaporated to yield a crude product (0.31 g) as an oil. This waschromatographed on a 50 g Biotage SNAP column with 4:1 DCM/EtOAc, then1:1 DCM/EtOAc. Fractions 76-96 contained the desired(S)-1-(2-(tert-butyldimethylsilyloxy)-1-(4-chloro-3-fluorophenyl)ethyl)-4-(5-fluoro-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one(0.08 g, 0.14 mmol, 31% yield) as a film.

Step B: 1M Tetrabutylammonium fluoride in THF (0.42 mL, 0.42 mmol) wasadded to(S)-1-(2-(tert-butyldimethylsilyloxy)-1-(4-chloro-3-fluorophenyl)ethyl)-4-(5-fluoro-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one(0.08 g, 0.14 mmol) in THF (10 mL). The mixture was stirred at roomtemperature. After 1 hour, the reaction mixture was evaporated, and theresidue was partitioned between dilute aqueous NaCl and EtOAc. The EtOAcwas washed with water, brine, dried over MgSO₄, filtered, and evaporatedto yield a crude product (0.10 g) as a film. The crude product waspurified by chromatography on a 10 g Biotage SNAP column with EtOAc.Fractions 13-23 contained the desired(S)-1-(1-(4-chloro-3-fluorophenyl)-2-hydroxyethyl)-4-(5-fluoro-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one(0.050 g, 0.11 mmol, 78% yield) as a glass. ¹H NMR (400 MHz, CDCl₃) δ8.24 (d, 1H), 7.42-7.37 (m, 2H), 7.25-7.19 (m, 2H), 7.12-7.08 (m, 1H),6.83-6.80 (m, 1H), 6.23-6.19 (m, 1H), 5.27-5.24 (m, 1H), 4.30-4.25 (m,1H), 4.15-4.09 (m, 1H), 4.03-3.95 (m, 3H), 3.57-3.50 (m, 2H), 2.05-2.00(m, 2H), 1.61-1.50 (m, 2H).

Example 17

(S)-1-(1-(3-chloro-4-fluorophenyl)-2-hydroxyethyl)-4-(2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one

Step A: 1.0M Potassium 2-methylpropan-2-olate in THF (2.02 mL, 2.02mmol) and tetrabutylammonium iodide (0.0573 g, 0.155 mmol) were added toa suspension of 4-(2-(methylthio)pyrimidin-4-yl)pyridin-2(1H)-one (0.340g, 1.55 mmol) in THF (20 mL) cooled in ice. After 10 minutes stirring inice, a solution of(R)-2-(tert-butyldimethylsilyloxy)-1-(3-chloro-4-fluorophenyl)ethylmethanesulfonate (1.07 g, 2.79 mmol) in THF (5 mL) was added. Themixture was heated at 60° C. overnight. The reaction mixture wasevaporated, and the residue partitioned between water and EtOAc. TheEtOAc was washed with brine, dried over MgSO₄, filtered, and evaporatedto yield a crude product (1.14 g) as an oil. This was chromatographed ona 50 g Biotage SNAP column with 4:1 DCM/EtOAc. Fractions 19-46 containedthe desired(S)-1-(2-(tert-butyldimethylsilyloxy)-1-(3-chloro-4-fluorophenyl)ethyl)-4-(2-(methylthio)pyrimidin-4-yl)pyridin-2(1H)-one(0.45 g, 0.889 mmol, 57.3% yield) as a film.

Step B: 3-Chlorobenzoperoxoic acid (0.46 g, 2.7 mmol) was added to(S)-1-(2-(tert-butyldimethylsilyloxy)-1-(3-chloro-4-fluorophenyl)ethyl)-4-(2-(methylthio)pyrimidin-4-yl)pyridin-2(1H)-one(0.45 g, 0.89 mmol) in DCM (20 mL). The mixture was stirred at roomtemperature for 3 hours. The reaction mixture was evaporated, and theresidue taken up in EtOAc, washed twice with a mixture of saturatedaqueous Na₂S₂O₃ and saturated aqueous NaHCO₃, brine, dried over MgSO₄,filtered, and evaporated to yield the desired(S)-1-(2-(tert-butyldimethylsilyloxy)-1-(3-chloro-4-fluorophenyl)ethyl)-4-(2-(methylsulfonyl)pyrimidin-4-yl)pyridin-2(1H)-one(0.48 g, 0.89 mmol, 100% yield) as a film.

Step C: Tetrahydro-2H-pyran-4-amine (0.45 g, 4.5 mmol) was added to(S)-1-(2-(tert-butyldimethylsilyloxy)-1-(3-chloro-4-fluorophenyl)ethyl)-4-(2-(methylsulfonyl)pyrimidin-4-yl)pyridin-2(1H)-one(0.48 g, 0.89 mmol) in DMA (4 mL) in a microwave vial. The mixture washeated at 120° C. for 1 hour in a microwave. The reaction mixture wasdiluted with water and extracted with EtOAc. The EtOAc was washed threetimes with dilute aqueous NaCl, water, twice with brine, dried overMgSO₄, filtered, and evaporated to yield the desired(S)-1-(2-(tert-butyldimethylsilyloxy)-1-(3-chloro-4-fluorophenyl)ethyl)-4-(2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one(0.46 g, 0.82 mmol, 92% yield) as a film.

Step D: 1M Tetrabutylammonium fluoride in THF (2.5 mL, 2.5 mmol) wasadded to(S)-1-(2-(tert-butyldimethylsilyloxy)-1-(3-chloro-4-fluorophenyl)ethyl)-4-(2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one(0.46 g, 0.82 mmol) in THF (40 mL). The mixture was stirred at roomtemperature. After 45 minutes, the reaction mixture was evaporated, andthe residue was partitioned between dilute aqueous NaCl and EtOAc. TheEtOAc was washed with water, brine, dried over MgSO₄, filtered, andevaporated to yield a crude product (0.43 g) as a film. The crudeproduct was purified by chromatography on a 50 g Biotage SNAP columnwith 10:1 EtOAc/MeOH. Fractions 19-29 contained the desired(S)-1-(1-(3-chloro-4-fluorophenyl)-2-hydroxyethyl)-4-(2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one(0.25 g, 0.56 mmol, 68% yield) as a solid foam. ¹H NMR (400 MHz, CDCl₃)δ 8.38 (d, 1H), 7.47-7.44 (m, 1H), 7.38 (d, 1H), 7.29-7.24 (m, 1H),7.18-7.14 (m, 1H), 6.88 (d, 1H), 6.80-6.77 (m, 1H), 6.21-6.17 (m, 1H),5.17-5.14 (m, 1H), 4.32-4.29 (m, 2H), 4.15-4.08 (m, 2H), 4.03-3.98 (m,2H), 3.60-3.52 (m, 2H), 2.70-2.66 (m, 1H), 2.09-2.03 (m, 2H), 1.63-1.53(m, 2H); m/z (APCI-pos) M+1=445.1; 81.6% e.e. by chiral HPLC (ChiralTech, column OD-H, 4.6 mm×250 mm, 5 u, 15% ethanol/85% hexanes, 1mL/minute).

Example 18

(S)-1-(1-(3-fluorophenyl)-2-hydroxyethyl)-4-(2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one

Step A: 1M Potassium 2-methylpropan-2-olate in THF (0.815 mL, 0.815mmol; solution) and tetrabutylammonium iodide (0.0251 g, 0.0679 mmol)were added to4-(2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one(0.185 g, 0.679 mmol) suspended in dioxane (10 mL) in a sealed vial.After 10 minutes stirring, a solution of(R)-2-(tert-butyldimethylsilyloxy)-1-(3-fluorophenyl)ethylmethanesulfonate (0.355 g, 1.02 mmol; prepared as described inIntermediate Example B substituting 3-fluorobenzaldehyde for4-chloro-3-fluorobenzaldehyde in Step A) in dioxane (2 mL) was added.The mixture was heated at 95° C. overnight. The reaction mixture wasdiluted with water and extracted with EtOAc. The EtOAc was washed withwater, brine, dried over MgSO₄, filtered, and evaporated to yield acrude product (0.45 g) as an oil. The crude product was chromatographedon a 50 g Biotage SNAP column with 4:1 EtOAc/hexane. Fractions 42-84contained the desired(S)-1-(2-(tert-butyldimethylsilyloxy)-1-(3-fluorophenyl)ethyl)-4-(2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one(0.14 g, 0.267 mmol, 39.3% yield) as a glass.

Step B: 1M Tetrabutylammonium fluoride in THF (0.800 mL, 0.800 mmol) to(S)-1-(2-(tert-butyldimethylsilyloxy)-1-(3-fluorophenyl)ethyl)-4-(2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one(0.14 g, 0.267 mmol) in THF (10 mL). The mixture was stirred at roomtemperature for 20 minutes. The reaction mixture was evaporated, and theresidue was partitioned between dilute aqueous NaCl and EtOAc. The EtOAcwas washed with water, brine, dried over MgSO₄, filtered, and evaporatedto yield a crude product (0.17 g) as a film. The crude product waspurified by chromatography on a 10 g Biotage SNAP column with 10:1EtOAc/MeOH. Fractions 7-11 contained the desired(S)-1-(1-(3-fluorophenyl)-2-hydroxyethyl)-4-(2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one(0.100 g, 0.244 mmol, 91.3% yield) as a film. ¹H NMR (400 MHz, CDCl₃) δ8.31 (d, 1H), 7.47 (d, 1H), 7.32-7.28 (m, 1H), 7.20-7.06 (m, 3H), 6.80(d, 1H), 6.78-6.76 (m, 1H), 6.38-6.34 (m, 1H), 5.34-5.31 (m, 1H),4.35-4.28 (m, 3H), 4.15-4.09 (m, 2H), 4.08-3.96 (m, 2H), 3.58-3.50 (m,2H), 2.07-2.00 (m, 2H), 1.62-1.51 (m, 2H); m/z (APCI-pos) M+1=411.1; 86%e.e. by chiral HPLC (Chiral Tech, column OD-H, 4.6 mm×250 mm, 5 u, 20%ethanol/80% hexanes, 1 mL/minute).

Example 19

(S)-1-(1-(2,3-difluorophenyl-2-hydroxyethyl)-4-(2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one

Step A: 1M Potassium 2-methylpropan-2-olate in THF (0.815 mL, 0.815mmol; solution) and tetrabutylammonium iodide (0.0251 g, 0.0679 mmol)were added to4-(2-(tetrahydro-2H-pyran-4-ylamino)pyrimidin-4-yl)pyridin-2(1H)-one(0.185 g, 0.679 mmol) suspended in dioxane (10 mL) in a sealed vial.After 10 minutes stirring, a solution of(R)-2-(tert-butyldimethylsilyloxy)-1-(2,3-difluorophenyl)ethylmethanesulfonate (0.355 g, 1.02 mmol; prepared as described inIntermediate Example B substituting 2,3-difluorobenzaldehyde for4-chloro-3-fluorobenzaldehyde in Step A) in dioxane (2 mL) was added.The mixture was heated at 95° C. overnight. The reaction mixture wasdiluted with water and extracted with EtOAc. The EtOAc was washed withwater, brine, dried over MgSO₄, filtered, and evaporated to yield acrude product (0.45 g) as an oil. The crude product was chromatographedon a 50 g Biotage SNAP column with 4:1 EtOAc/hexane. Fractions 42-84contained the desired(S)-1-(2-(tert-butyldimethylsilyloxy)-1-(2,3-difluorophenyl)ethyl)-4-(2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one(0.14 g, 0.267 mmol, 39.3% yield) as a glass.

Step B: 1M Tetrabutylammonium fluoride in THF (1.00 mL, 1.00 mmol) wasadded to(S)-1-(2-(tert-butyldimethylsilyloxy)-1-(2,3-difluorophenyl)ethyl)-4-(2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one(0.18 g, 0.33 mmol) in THF (10 mL). The mixture was stirred at roomtemperature for 20 minutes. The reaction mixture was evaporated, and theresidue was partitioned between dilute aqueous NaCl and EtOAc. The EtOAcwas washed with water, brine, dried over MgSO₄, filtered, and evaporatedto yield a crude product (0.15 g) as a film. The crude product waspurified by chromatography on a 10 g Biotage SNAP column with 10:1EtOAc/MeOH. Fractions 7-11 contained the desired(S)-1-(1-(2,3-difluorophenyl)-2-hydroxyethyl)-4-(2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one(0.091 g, 0.21 mmol, 64% yield) as a film. ¹H NMR (400 MHz, CDCl₃) δ8.31 (d, 1H), 7.43 (d, 1H), 7.36-7.28 (m, 1H), 7.15-7.08 (m, 3H),7.04-6.98 (m, 1H), 6.80 (d, 1H), 6.77-6.74 (m, 1H), 6.30-6.26 (m, 1H),5.46-5.43 (m, 1H), 4.41 (br s, 1H), 4.32-4.23 (m, 2H), 4.25-4.19 (m,2H), 4.18-4.02 (m, 1H), 4.02-3.96 (m, 1H), 3.57-3.50 (m, 2H), 2.06-2.00(m, 2H), 1.62-1.51 (m, 2H); m/z (APCI-pos) M+1=429.1; 83% e.e. by chiralHPLC (Chiral Tech, column OD-H, 4.6 mm×250 mm, 5 u, 20% ethanol/80%hexanes, 1 mL/minute).

Example 20

(S)-1-(1-(4-chloro-3-fluorophenyl)-2-hydroxyethyl)-5-fluoro-4-(2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one

Step A: Sodium carbonate (1.6 g, 15 mmol) was added to5-fluoro-2-methoxypyridin-4-ylboronic acid (1.0 g, 6.0 mmol) and2,4-dichloropyrimidine (0.75 g, 5.0 mmol) in 4:1 dioxane/water (25 mL),and the suspension was purged with argon. PdCl₂(dppf)*DCM (0.21 g, 0.25mmol) was added, and the mixture was heated at 80° C. under argonovernight. The reaction mixture was diluted with water, and theresulting solid was collected by vacuum filtration, washed with water,and dried to provide the desired2-chloro-4-(5-fluoro-2-methoxypyridin-4-yl)pyrimidine (1.2 g, 5.0 mmol,99% yield) as a solid.

Step B: Tetrahydro-2H-pyran-4-amine (0.101 g, 1.00 mmol) andN-ethyl-N-isopropylpropan-2-amine (0.188 mL, 1.08 mmol) were added to2-chloro-4-(5-fluoro-2-methoxypyridin-4-yl)pyrimidine (0.20 g, 0.835mmol) dissolved in 2-butanol (5 mL) in a vial. The vial was sealed andheated at 100° C. overnight. The mixture was evaporated, and the darkresidue was partitioned between EtOAc and water. The EtOAc was washedwith brine, dried over MgSO₄, filtered, and evaporated to yield a crudeproduct (0.25 g) as an oil. This was chromatographed on a 50 g BiotageSNAP column with 2:1 EtOAc/hexane. Fractions 22-48 contained the desired4-(5-fluoro-2-methoxypyridin-4-yl)-N-(tetrahydro-2H-pyran-4-yl)pyrimidin-2-amine(0.0992 g, 0.326 mmol, 39.1% yield) as a solid.

Step C: Iodotrimethylsilane (0.186 mL, 1.30 mmol) was added dropwise toa solution of4-(5-fluoro-2-methoxypyridin-4-yl)-N-(tetrahydro-2H-pyran-4-yl)pyrimidin-2-amine(0.0992 g, 0.3260 mmol) in acetonitrile (6 mL) in a vial at roomtemperature. The sealed vial was heated at 80° C. overnight. Thereaction mixture was treated with MeOH (about 2 mL) and some saturatedaqueous NaHCO₃. The mixture was concentrated, and the aqueous residuewas treated dropwise with 1M HCl until a tan precipitate formed (pH 2).This was extracted with 2 portions 10% isopropyl alcohol (“IPA”) in DCM.The combined organics were dried over MgSO₄, filtered, and evaporated toyield5-fluoro-4-(2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one(0.0293 g, 0.1009 mmol, 30.96% yield) as a solid.

Step D: Tetrabutylammonium iodide (0.00186 g, 0.00505 mmol) and 1Mpotassium 2-methylpropan-2-olate in THF (0.121 mL, 0.121 mmol) wereadded to5-fluoro-4-(2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one(0.0293 g, 0.101 mmol) in THF (3 mL). After 10 minutes stirring at roomtemperature, a solution of(R)-2-(tert-butyldimethylsilyloxy)-1-(4-chloro-3-fluorophenyl)ethylmethanesulfonate (0.0541 g, 0.141 mmol) in THF (2 mL) was added. Themixture was heated at reflux for 2 hours. The reaction mixture waspartitioned between water and EtOAc. The EtOAc was washed with brine,dried over MgSO₄, filtered, and evaporated to yield a crude product(0.12 g) as a film. This was chromatographed on a 1 g Sep-pack columnwith 1:1 hexane/EtOAc. Fractions 8-16 contained the desired(S)-1-(2-(tert-butyldimethylsilyloxy)-1-(4-chloro-3-fluorophenyl)ethyl)-5-fluoro-4-(2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one(0.0036 g, 0.00624 mmol, 6.18% yield).

Step E: 1M Tetrabutylammonium fluoride in THF (0.019 mL, 0.019 mmol) wasadded to(S)-1-(2-(tert-butyldimethylsilyloxy)-1-(4-chloro-3-fluorophenyl)ethyl)-5-fluoro-4-(2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one(0.0036 g, 0.0062 mmol) in THF (1 mL). After 10 minutes, the reactionmixture was evaporated, and the residue was partitioned between EtOAcand dilute NaCl. The EtOAc was washed with brine, dried over MgSO₄,filtered, and evaporated to yield a crude product (0.0092 g) as a film.This was chromatographed on a 1 g silica Sep-pack with 10:1 EtOAc/MeOH.Fractions 2-4 contained the desired(S)-1-(1-(4-chloro-3-fluorophenyl)-2-hydroxyethyl)-5-fluoro-4-(2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one(0.0018 g, 0.0039 mmol, 62% yield) as a film. ¹H NMR (400 MHz, CDCl₃) δ8.38 (d, 1H), 7.46-7.42 (m, 1H), 7.34 (d, 1H), 7.27-7.20 (m, 2H),7.14-7.11 (m, 1H), 6.93-6.90 (m, 1H), 6.20-6.12 (m, 1H), 5.22-5.19 (m,1H), 4.31 (d, 2H), 4.15-4.09 (m, 2H), 4.03-3.97 (m, 2H), 3.60-3.53 (m,2H), 2.09-2.03 (m, 2H), 1.63-1.55 (m, 2H); m/z (APCI-pos) M+1=463.1.

Example 21

(S)-1-(1-(4-chloro-3-fluorophenyl)-2-hydroxyethyl)-3-fluoro-4-(2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one

Step A: Sodium carbonate (2.13 g, 20.1 mmol) was added to2-chloro-3-fluoropyridin-4-ylboronic acid (1.41 g, 8.05 mmol) and2,4-dichloropyrimidine (1.0 g, 6.71 mmol) in 4:1 dioxane/water (50 mL),and the mixture was sparged with argon. PdCl₂(dppf)*DCM (0.274 g, 0.336mmol) was added, and the mixture was heated at 80° C. under argon. After4.5 hours, more boronic acid (approximately 0.2 g) was added and heatingcontinued for a total of 8.5 hours. The reaction mixture was dilutedwith water, and the resulting solid was collected by vacuum filtrationto afford the desired2-chloro-4-(2-chloro-3-fluoropyridin-4-yl)pyrimidine (1.18 g, 4.84 mmol,72.0% yield) with minor impurities.

Step B: N-Ethyl-N-isopropylpropan-2-amine (0.185 mL, 1.07 mmol) andtetrahydro-2H-pyran-4-amine (0.0912 g, 0.901 mmol) were added to2-chloro-4-(2-chloro-3-fluoropyridin-4-yl)pyrimidine (0.200 g, 0.819mmol) in 2-butanol (7 mL) in a vial. The vial was sealed and heated at80° C. overnight. The reaction mixture was evaporated, and the residuewas partitioned between EtOAc and water. The EtOAc was washed withbrine, dried over MgSO₄, filtered, and evaporated to yield a crudeproduct (0.25 g) as a film. This was chromatographed on a 10 g BiotageSNAP column with EtOAc. Fractions 8-13 contained the desired4-(2-chloro-3-fluoropyridin-4-yl)-N-(tetrahydro-2H-pyran-4-yl)pyrimidin-2-amine(0.08 g, 0.259 mmol, 31.6% yield) as a solid.

Step C:4-(2-Chloro-3-fluoropyridin-4-yl)-N-(tetrahydro-2H-pyran-4-yl)pyrimidin-2-amine(0.08 g, 0.259 mmol) and 1M HCl (3.89 mL, 3.89 mmol) were added to amicrowave vial. The vial was heated in a microwave at 140° C. for atotal of 10 hours in 2 hour segments. The reaction mixture was dilutedwith water, and the desired3-fluoro-4-(2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one(0.0565 g, 0.195 mmol, 75.1% yield) was collected by vacuum filtration.

Step D: 1M KHMDS in THF (0.234 mL, 0.234 mmol) was added to3-fluoro-4-(2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one(0.0565 g, 0.195 mmol) suspended in 2-methyltetrahydrofuran (5 mL)cooled in ice. The mixture was stirred for 10 minutes at roomtemperature. Then, a solution of(R)-2-(tert-butyldimethylsilyloxy)-1-(4-chloro-3-fluorophenyl)ethylmethanesulfonate (0.112 g, 0.292 mmol) in 2-methyltetrahydrofuran (2 mL)was added, and the mixture was heated at 80-90° C. for 2 days. Thecooled reaction mixture was evaporated. The residue was treated withdilute NaCl and EtOAc, filtered to remove solids, and the layers wereseparated. The EtOAc was washed with brine, dried over MgSO₄, filtered,and evaporated to yield a crude product (0.09 g) as a film. This waschromatographed on a 10 g Biotage SNAP column with 2:1 EtOAc/hexane.Fractions 12-16 contained the desired(S)-1-(2-(tert-butyldimethylsilyloxy)-1-(4-chloro-3-fluorophenyl)ethyl)-3-fluoro-4-(2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one(0.02 g, 0.0347 mmol, 17.8% yield) as a glass.

Step E: 1M Tetrabutylammonium fluoride in THF (0.10 mL, 0.10 mmol) wasadded to(S)-1-(2-(tert-butyldimethylsilyloxy)-1-(4-chloro-3-fluorophenyl)ethyl)-3-fluoro-4-(2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one(0.02 g, 0.035 mmol) in THF (5 mL). After 30 minutes, the reactionmixture was evaporated, and the residue was partitioned between EtOAcand dilute NaCl. The EtOAc was washed with brine, dried over MgSO₄,filtered, and evaporated to yield a crude product (0.02 g) as a film.This was chromatographed on a Biotage 10 g SNAP column with EtOAc.Fractions 23-33 contained the desired(S)-1-(1-(4-chloro-3-fluorophenyl)-2-hydroxyethyl)-3-fluoro-4-(2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one(0.0018 g, 0.0039 mmol, 11% yield) as a film. ¹H NMR (400 MHz, CDCl₃) δ8.41 (d, 1H), 7.45-7.40 (m, 1H), 7.24-7.18 (m, 2H), 7.14-7.10 (m, 2H),6.81-6.77 (m, 1H), 6.23-6.20 (m, 1H), 5.14-5.12 (m, 1H), 4.34-4.31 (m,2H), 4.15-4.04 (m, 2H), 4.03-3.97 (m, 2H), 3.58-3.51 (m, 2H), 2.09-2.03(m, 2H), 1.63-1.53 (m, 2H); m/z (APCI-pos) M+1=463.1.

Example 22

1-((S)-1-(3-chlorophenyl)-2-hydroxyethyl)-4-(2-(((3S,4S)-3-fluorotetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one

Step A: 1M KHMDS in THF (5.47 mL, 5.47 mmol) was added to a suspensionof 4-(2-(methylthio)pyrimidin-4-yl)pyridin-2(1H)-one (1.00 g, 4.56 mmol)in 2-methyltetrahydrofuran (15 mL) cooled in ice. After stirring 15minutes at room temperature, a solution of(R)-2-(tert-butyldimethylsilyloxy)-1-(3-chlorophenyl)ethylmethanesulfonate (2.33 g, 6.39 mmol; prepared as described inIntermediate Example B, substituting 1-chloro-3-vinylbenzene for1-chloro-2-fluoro-4-vinylbenzene in Step B) in 2-methyltetrahydrofuran(5 mL) was added to the mixture and heated at 80° C. for 48 hours. Thereaction mixture was evaporated, and the residue was partitioned betweenwater and EtOAc. The EtOAc was washed with water, brine, dried overMgSO₄, filtered, and evaporated to yield a crude product (2.22 g) as asolid. This was chromatographed on a 50 g Biotage SNAP column with 1:1hexane/EtOAc. Fractions 12-30 contained(S)-1-(2-(tert-butyldimethylsilyloxy)-1-(3-chlorophenyl)ethyl)-4-(2-(methylthio)pyrimidin-4-yl)pyridin-2(1H)-one(0.86 g, 1.76 mmol, 38.6% yield) as a solid foam.

Step B: 3-Chlorobenzoperoxoic acid (0.91 g, 5.3 mmol) was added to(S)-1-(2-(tert-butyldimethylsilyloxy)-1-(3-chlorophenyl)ethyl)-4-(2-(methylthio)pyrimidin-4-yl)pyridin-2(1H)-one(0.86 g, 1.8 mmol) in DCM (20 mL) cooled in ice. The mixture was stirredat room temperature for 2 hours. The reaction mixture was diluted withDCM, washed twice with a mixture of saturated aqueous NaHCO₃ andsaturated aqueous Na₂S₂O₃, water, dried over MgSO₄, filtered, andevaporated to yield(S)-1-(2-(tert-butyldimethylsilyloxy)-1-(3-chlorophenyl)ethyl)-4-(2-(methylsulfonyl)pyrimidin-4-yl)pyridin-2(1H)-one(0.83 g, 1.6 mmol, 91% yield).

Step C:(S)-1-(2-(tert-Butyldimethylsilyloxy)-1-(3-chlorophenyl)ethyl)-4-(2-(methylsulfonyl)pyrimidin-4-yl)pyridin-2(1H)-one(0.200 g, 0.385 mmol) and 2-butanol (2 mL) were added to a vial.N-Ethyl-N-isopropylpropan-2-amine (0.0999 mL, 0.577 mmol) and(3S,4S)-3-fluorotetrahydro-2H-pyran-4-amine (0.0596 g, 0.500 mmol) wereadded to the solution. The vial was sealed and heated at 120° C. for 40hours. The reaction mixture was evaporated, and the residue partitionedbetween water and EtOAc. The EtOAc was washed with brine, dried overMgSO₄, filtered, and evaporated to yield a crude product (0.20 g) as afilm. This was chromatographed on a 10 g Biotage SNAP column with EtOAc.Fractions 9-18 contained1-((S)-2-(tert-butyldimethylsilyloxy)-1-(3-chlorophenyl)ethyl)-4-(2-(((3S,4S)-3-fluorotetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one(0.105 g, 0.188 mmol, 48.8% yield) as a glass.

Step D: 4M HCl in dioxane (0.939 mL, 3.76 mmol) was added to1-((S)-2-(tert-butyldimethylsilyloxy)-1-(3-chlorophenyl)ethyl)-4-(2-(((3S,4S)-3-fluorotetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one(0.105 g, 0.188 mmol) in MeOH (5 mL). After 30 minutes, the reactionmixture was evaporated, and the residue was partitioned between EtOAcand saturated aqueous NaHCO₃. The EtOAc was washed with brine, driedover MgSO₄, filtered, and evaporated to yield a crude product (0.08 g)as a film. This was chromatographed on a 10 g Biotage SNAP column with10:1 EtOAc/i-PrOH. Fractions 9-16 contained1-((S)-1-(3-chlorophenyl)-2-hydroxyethyl)-4-(2-(((3S,4S)-3-fluorotetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-oneas a solid foam. ¹H NMR (400 MHz, CD₃OD) δ 8.38 (d, 1H), 7.80 (d, 1H),7.41-7.39 (m, 1H), 7.38-7.28 (m, 2H), 7.22 (d, 1H), 7.09 (d, 1H),7.00-6.97 (m, 1H), 6.15-6.11 (m, 1H), 4.83-4.70 (m, 1H), 4.34-4.25 (m,2H), 4.20-4.15 (m, 1H), 4.01-3.98 (m, 1H), 3.94-3.88 (m, 1H), 3.70-3.54(m, 2H), 2.08-1.95 (m, 1H), 1.83-1.77 (m, 1H) 1.13 (d, 1H); m/z(APCI-pos) M+1=445.1; 97.5% e.e. by chiral HPLC (Chiral Tech, columnOD-H, 4.6 mm×250 mm, 5 u, 20% ethanol/80% hexanes, 1 mL/minute).

Example 23

1-((S)-1-(3-chlorophenyl)-2-hydroxyethyl)-4-(2-(((3S,4R)-3-fluorotetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one

1-((S)-1-(3-Chlorophenyl)-2-hydroxyethyl)-4-(2-(((3S,4R)-3-fluorotetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-onewas prepared as described in Example 22, substituting(3S,4R)-3-fluorotetrahydro-2H-pyran-4-amine for(3S,4S)-3-fluorotetrahydro-2H-pyran-4-amine in Step C. ¹H NMR (400 MHz,CD₃OD) δ 8.39 (d, 1H), 7.83 (d, 1H), 7.43-7.41 (m, 1H), 7.38-7.27 (m,3H), 7.26 (d, 1H), 7.10 (d, 1H), 7.02 (dd, 1H), 6.14 (dd, 1H), 4.62-4.44(m, 1H), 4.36-4.26 (m, 2H), 4.22-4.17 (m, 1H), 4.07-3.86 (m, 1H),3.60-3.44 (m, 2H), 2.22-2.14 (m, 1H), 1.73-1.63 (m, 1H) 1.15 (d, 1H);m/z (APCI-pos) M+1=445.1; 99% e.e. by chiral HPLC (Chiral Tech, columnOD-H, 4.6 mm×250 mm, 5 u, 20% ethanol/80% hexanes, 1 mL/minute).

Example 24

(S)-1-(1-(4-chloro-3-fluorophenyl)-2-hydroxyethyl)-4-(2-((2-methylpyrimidin-4-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one

Step A: 2-Methylpyrimidin-4-amine (0.41 g, 3.7 mmol) and(S)-1-(2-(tert-butyldimethylsilyloxy)-1-(4-chloro-3-fluorophenyl)ethyl)-4-(2-(methylsulfonyl)pyrimidin-4-yl)pyridin-2(1H)-one(0.10 g, 0.19 mmol) were placed in sec-BuOH (1 mL), heated to 110° C. ina sealed tube for 18 hours, then poured into water, and extracted withDCM. The combined organic fractions were dried (MgSO₄), filtered, andconcentrated to give the crude product, which was purified by columnchromatography (500:5 DCM/MeOH to remove impurity, then 500:15 forproduct) to give(S)-1-(2-(tert-butyldimethylsilyloxy)-1-(4-chloro-3-fluorophenyl)ethyl)-4-(2-((2-methylpyrimidin-4-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one(0.034 g, 32% yield).

Step B:(S)-1-(2-(tert-Butyldimethylsilyloxy)-1-(4-chloro-3-fluorophenyl)ethyl)-4-(2-((2-methylpyrimidin-4-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one(0.034 g, 0.060 mmol) was placed in THF (5 mL) at room temperature.Tetra-n-butylammonium fluoride (“TBAF”) (0.18 mL, 0.18 mmol) was addedto the mixture. The mixture was stirred for 1 hour, then poured intowater, and extracted with DCM. The combined organic fractions were dried(MgSO₄), filtered, and concentrated to give the crude product, which waspurified by column chromatography (0-5.5% MeOH in DCM) to give theproduct(S)-1-(1-(4-chloro-3-fluorophenyl)-2-hydroxyethyl)-4-(2-((2-methylpyrimidin-4-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one(0.005 g, 18% yield). m/z (APCI-pos) M+1=453.

Example 25

(S)-1-(1-(4-chloro-3-fluorophenyl)-2-hydroxyethyl)-4-(2-((6-methylpyrimidin-4-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one

(S)-1-(1-(4-Chloro-3-fluorophenyl)-2-hydroxyethyl)-4-(2-((6-methylpyrimidin-4-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-onewas prepared according to Example 24, substituting6-methylpyrimidin-4-amine for 2-methylpyrimidin-4-amine in Step A. m/z(APCI-pos) M+1=453.

Example 26

(S)-1-(1-(4-chloro-3-fluorophenyl)-2-hydroxyethyl)-4-(2-((6-methoxypyrimidin-4-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one

(S)-1-(1-(4-Chloro-3-fluorophenyl)-2-hydroxyethyl)-4-(2-((6-methoxypyrimidin-4-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-onewas prepared according to Example 24, substituting6-methoxypyrimidin-4-amine for 2-methylpyrimidin-4-amine in Step A. m/z(APCI-pos) M+1=469.

Example 27

(S)-1-(1-(4-chloro-3-fluorophenyl)-2-hydroxyethyl)-4-(2-((2-methylpyridin-4-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one

Step A: 2-Methylpyridin-4-amine (0.28 g, 2.6 mmol) was placed in THF (5mL) and cooled to −78° C. t-BuLi (1.5 mL, 2.6 mmol) was added dropwise,and the solution was warmed to 0° C. for 30 minutes. This solution wasthen added dropwise to a −78° C. THF solution (5 mL) of(S)-1-(2-(tert-butyldimethylsilyloxy)-1-(4-chloro-3-fluorophenyl)ethyl)-4-(2-(methylsulfonyl)pyrimidin-4-yl)pyridin-2(1H)-one(0.070 g, 0.13 mmol). The reaction was stirred for an additional 30minutes at −78° C., then poured into water, and extracted with DCM. Thecombined organic fractions were dried (MgSO₄), filtered, andconcentrated to give the crude product, which was purified by columnchromatography (500:10-500:20 DCM/MeOH) to give the product(S)-1-(2-(tert-butyldimethylsilyloxy)-1-(4-chloro-3-fluorophenyl)ethyl)-4-(2-((2-methylpyridin-4-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one(0.028 g, 38% yield).

Step B:(S)-1-(2-(tert-Butyldimethylsilyloxy)-1-(4-chloro-3-fluorophenyl)ethyl)-4-(2-((2-methylpyridin-4-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one(0.028 g, 0.049 mmol) was placed in THF (5 mL). TBAF (0.054 mL, 0.054mmol) was then added, and the reaction was stirred for 1 hour, thenpoured into water, and extracted with DCM. The combined organicfractions were dried (MgSO₄), filtered, and concentrated to give thecrude product, which was purified by column chromatography(500:40-500:50 DCM/MeOH) to give the product(S)-1-(1-(4-chloro-3-fluorophenyl)-2-hydroxyethyl)-4-(2-((2-methylpyridin-4-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one(0.005 g, 22% yield). m/z (APCI-pos) M+1=452.

Example 28

(S)-1-(1-(4-chloro-3-fluorophenyl)-2-hydroxyethyl)-4-(2-((1,3-dimethyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one

Step A:(S)-1-(2-(tert-Butyldimethylsilyloxy)-1-(4-chloro-3-fluorophenyl)ethyl)-4-(2-(methylsulfonyl)pyrimidin-4-yl)pyridin-2(1H)-one(0.100 g, 0.186 mmol) and 1,3-dimethyl-1H-pyrazol-4-amine (0.413 g, 3.72mmol) were placed in s-BuOH (2 mL), heated to 110° C. overnight, thenpoured into water and extracted with DCM. The combined organic fractionswere dried (MgSO₄), filtered, and concentrated to give the crudeproduct, which was purified by column chromatography (500:10 DCM/MeOH)to give the product(S)-1-(2-(tert-butyldimethylsilyloxy)-1-(4-chloro-3-fluorophenyl)ethyl)-4-(2-((1,3-dimethyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one(0.070 g, 66.2% yield).

Step B:(S)-1-(2-(tert-Butyldimethylsilyloxy)-1-(4-chloro-3-fluorophenyl)ethyl)-4-(2-((1,3-dimethyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one(0.070 g, 0.12 mmol) was placed in THF (3 mL). TBAF (0.14 mL, 0.14 mmol)was added, and the mixture was stirred for 1 hour, then poured intowater, and extracted with DCM. The combined organic fractions were dried(MgSO₄), filtered, and concentrated to give the crude product, which waspurified by column chromatography (500:20-500:30 DCM/MeOH) to give theproduct(S)-1-(1-(4-chloro-3-fluorophenyl)-2-hydroxyethyl)-4-(2-((1,3-dimethyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one(0.040 g, 71% yield). m/z (APCI-pos) M+1=455.

Example 29

(S)-1-(1-(4-chloro-3-fluorophenyl)-2-hydroxyethyl)-4-(2-((2-methoxypyridin-4-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one

(S)-1-(1-(4-Chloro-3-fluorophenyl)-2-hydroxyethyl)-4-(2-((2-methoxypyridin-4-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-onewas prepared according to Example 27, substituting2-methoxypyridin-4-amine for 2-methylpyridin-4-amine in Step A. m/z(APCI-pos) M+1=468.

Example 30

(S)-1-(1-(3,4-dichlorophenyl)-2-hydroxyethyl)-4-(2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one

Step A:(S)-1-(2-(tert-Butyldimethylsilyloxy)-1-(3,4-dichlorophenyl)ethyl)-4-(2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-onewas prepared according to the general procedure of Example 1, Step Asubstituting(S)-1-(2-(tert-butyldimethylsilyloxy)-1-(3,4-dichlorophenyl)ethyl)-4-(2-(methylsulfonyl)pyrimidin-4-yl)pyridin-2(1H)-onefor1-(2-(tert-butyldimethylsilyloxy)-1-(4-chloro-3-fluorophenyl)ethyl)-4-(2-(methylsulfonyl)pyrimidin-4-yl)pyridin-2(1H)-one.m/z (APCI-pos) M+1=575.2, 577.2.

Step B:(S)-1-(1-(3,4-Dichlorophenyl)-2-hydroxyethyl)-4-(2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one(43%, 2 steps) was prepared according to the general procedure ofExample 1, Step B, substituting(S)-1-(2-(tert-butyldimethylsilyloxy)-1-(3,4-dichlorophenyl)ethyl)-4-(2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-onefor(S)-1-(2-(tert-butyldimethylsilyloxy)-1-(4-chloro-3-fluorophenyl)ethyl)-4-(2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one.¹H NMR (400 MHz, (CD₃)₂SO) δ 8.42-8.41 (d, J=5.1 Hz, 1H), 7.92-7.90 (d,J=7.4 Hz, 1H), 7.64-7.62 (m, 2H), 7.36-7.34 (d, J=6.9 Hz, 1H), 7.31-7.28(d, J=10.6 Hz, 1H), 7.16-7.14 (d, J=5.1 Hz, 1H), 7.10 (s, 1H), 6.89-6.87(d, J=5.9 Hz, 1H), 5.97-5.93 (t, 1H), 5.34-5.31 (t, 1H), 4.19-4.13 (m,1H), 4.08-3.96 (m, 2H), 3.89-3.86 (m, 2H), 3.43-3.37 (t, 2H), 1.87-1.84(m, 2H), 1.59-1.48 (m, 2H); m/z (APCI-pos) M+1=461.1, 463.1.

Example 31

(S)-1-(1-(3,5-dichlorophenyl)-2-hydroxyethyl)-4-(2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one

Step A:(S)-1-(2-(tert-Butyldimethylsilyloxy)-1-(3,5-dichlorophenyl)ethyl)-4-(2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-onewas prepared according to the general procedure of Example 1, Step A,substituting(S)-1-(2-(tert-butyldimethylsilyloxy)-1-(3,5-dichlorophenyl)ethyl)-4-(2-(methylsulfonyl)pyrimidin-4-yl)pyridin-2(1H)-onefor1-(2-(tert-butyldimethylsilyloxy)-1-(4-chloro-3-fluorophenyl)ethyl)-4-(2-(methylsulfonyl)pyrimidin-4-yl)pyridin-2(1H)-one.m/z (APCI-pos) M+1=575.2, 577.2.

Step B:(S)-1-(1-(3,5-Dichlorophenyl)-2-hydroxyethyl)-4-(2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one(60%, 2 steps) was prepared according to the general procedure ofExample 1, Step B, substituting(S)-1-(2-(tert-butyldimethylsilyloxy)-1-(3,5-dichlorophenyl)ethyl)-4-(2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-onefor(S)-1-(2-(tert-butyldimethylsilyloxy)-1-(4-chloro-3-fluorophenyl)ethyl)-4-(2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one.¹H NMR (400 MHz, (CD₃)₂SO) δ 8.43-8.41 (d, J=5.1 Hz, 1H), 7.96-7.94 (d,J=7.5 Hz, 1H), 7.57 (s, 1H), 7.39-7.38 (d, J=1.7 Hz, 2H), 7.36-7.34 (d,J=7.5 Hz, 1H), 7.17-7.15 (d, J=5.1 Hz, 1H), 7.11-7.10 (d, J=1.5 Hz, 1H),5.94-5.91 (t, 1H), 5.36-5.33 (t, 1H), 4.21-4.14 (m, 1H), 4.09-3.95 (m,2H), 3.89-3.86 (m, 2H), 3.43-3.37 (t, 2H), 1.88-1.84 (m, 2H), 1.58-1.49(m, 2H); m/z (APCI-pos) M+1=461.1, 463.1.

Example 32

1-((S)-1-(3,5-dichlorophenyl)-2-hydroxyethyl)-4-(2-(((3S,4R)-3-fluorotetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one

Step A:1-((S)-2-(tert-Butyldimethylsilyloxy)-1-(3,5-dichlorophenyl)ethyl)-4-(2-(((3S,4R)-3-fluorotetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-onewas prepared according to the general procedure of Example 3, Step A,substituting(S)-1-(2-(tert-butyldimethylsilyloxy)-1-(3,5-dichlorophenyl)ethyl)-4-(2-(methylsulfonyl)pyrimidin-4-yl)pyridin-2(1H)-onefor(S)-1-(2-(tert-butyldimethylsilyloxy)-1-(4-chloro-3-fluorophenyl)ethyl)-4-(2-(methylsulfonyl)pyrimidin-4-yl)pyridin-2(1H)-one.m/z (APCI-pos) M+1=593.2, 595.2.

Step B:1-((S)-1-(3,5-Dichlorophenyl)-2-hydroxyethyl)-4-(2-(((3S,4R)-3-fluorotetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one(52%, 2 steps) was prepared according to the general procedure ofExample 3, Step B, substituting1-((S)-2-(tert-butyldimethylsilyloxy)-1-(3,5-dichlorophenyl)ethyl)-4-(2-(((3S,4R)-3-fluorotetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-onefor1-((S)-2-(tert-butyldimethylsilyloxy)-1-(4-chloro-3-fluorophenyl)ethyl)-4-(2-(((3S,4S)-3-fluorotetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one.¹H NMR (400 MHz, (CD₃)₂SO) δ 8.45-8.44 (d, J=5.0 Hz, 1H), 7.97-7.95 (d,J=7.3 Hz, 1H), 7.63-7.61 (d, J=7.9 Hz, 1H), 7.58-7.57 (t, 1H), 7.39-7.38(d, J=1.9 Hz, 2H), 7.22-7.21 (d, J=5.0 Hz, 1H), 7.13-7.12 (d, J=1.9 Hz,1H), 6.92-6.90 (m, 1H), 5.95-5.91 (t, 1H), 5.36-5.33 (t, 1H), 4.66-4.49(m, 1H), 4.31-4.15 (m, 2H) 4.09-3.97 (m, 2H), 3.85-3.81 (m, 1H),3.51-3.40 (m, 2H), 2.04-2.01 (m, 1H), 1.63-1.57 (m, 1H); m/z (APCI-pos)M+1=479.0, 481.1.

Example 33

1-((S)-1-(3,5-dichlorophenyl-2-hydroxyethyl)-4-(2-(((3S,4S)-3-fluorotetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one

Step A:1-((S)-2-(tert-Butyldimethylsilyloxy)-1-(3,5-dichlorophenyl)ethyl)-4-(2-(((3S,4S)-3-fluorotetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-onewas prepared according to the general procedure of Example 2, Step A,substituting(S)-1-(2-(tert-butyldimethylsilyloxy)-1-(3,5-dichlorophenyl)ethyl)-4-(2-(methylsulfonyl)pyrimidin-4-yl)pyridin-2(1H)-onefor(S)-1-(2-(tert-butyldimethylsilyloxy)-1-(4-chloro-3-fluorophenyl)ethyl)-4-(2-(methylsulfonyl)pyrimidin-4-yl)pyridin-2(1H)-one.m/z (APCI-pos) M+1=593.1, 595.1.

Step B:1-((S)-1-(3,5-Dichlorophenyl)-2-hydroxyethyl)-4-(2-(((3S,4S)-3-fluorotetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one(59%, 2 steps) was prepared according to the general procedure ofExample 2, Step B, substituting1-((S)-2-(tert-butyldimethylsilyloxy)-1-(3,5-dichlorophenyl)ethyl)-4-(2-(((3S,4S)-3-fluorotetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-onefor1-((S)-2-(tert-butyldimethylsilyloxy)-1-(4-chloro-3-fluorophenyl)ethyl)-4-(2-(((3S,4S)-3-fluorotetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one.¹H NMR (400 MHz, (CD₃)₂SO) δ 8.46-8.45 (d, J=5.1 Hz, 1H), 7.96-7.94 (d,J=7.4 Hz, 1H), 7.58-7.57 (t, 1H), 7.41-7.38 (m, 3H), 7.24-7.23 (d, J=5.0Hz, 1H), 7.13-7.12 (d, J=2.1 Hz, 1H), 6.93-6.91 (m, 1H), 5.95-5.91 (t,1H), 5.36-5.33 (t, 1H), 4.86-4.73 (d, J=51.7 Hz, 1H), 4.25-4.15 (m, 2H),4.09-3.89 (m, 3H), 3.66-3.48 (m, 2H), 2.02-1.92 (m, 1H), 1.69-1.65 (m,1H); m/z (APCI-pos) M+1=479.0, 481.0.

Example 34

1-((4-chloro-3-fluorophenyl)(oxazol-5-yl)methyl)-4-(2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one

Step A: (4-Chloro-3-fluorophenyl)magnesium bromide (40.6 mL, 20.3 mmol;0.5M in THF) was added dropwise by syringe to a stirred solution ofoxazole-5-carbaldehyde (1.97 g, 20.3 mmol) in THF (40 mL) at 0° C. undernitrogen. The reaction was allowed to warm to room temperature and thenstirred for 30 minutes at room temperature. TLC in 1/1 ethylacetate/hexanes showed near complete consumption of starting material,and a new slightly lower rf spot as major. The reaction was quenched bycareful addition of saturated ammonium chloride solution by pipet withstirring. An ammonium chloride (50 mL) solution was added. The majorityof the THF was then removed by rotovap. The residual aqueous suspensionwas diluted with ethyl acetate (100 mL) and water (50 mL), transferredto a separatory funnel and shaken. The layers were separated, and theorganics were isolated and washed with brine (100 mL), dried (MgSO₄),filtered and concentrated to an oil. The crude product was loaded onto aBiotage 40M column with 2/3 ethyl acetate/hexanes and eluted. Productcontaining fractions were pooled and concentrated to a solid,(4-chloro-3-fluorophenyl)(oxazol-5-yl)methanol (4 g, 86%).

Step B: N,N-Diisopropylethylamine (“DIEA”) (174 μL, 0.997 mmol; d 0.742)was added neat by syringe to a stirred solution of(4-chloro-3-fluorophenyl)(oxazol-5-yl)methanol (227 mg, 0.997 mmol) indichloromethane (3 mL) at 0° C. under nitrogen, followed by addition ofmethane sulfonyl chloride (77.5 μL, 0.997 mmol) neat by syringe. After 1hour, TLC in 2/3 ethyl acetate/hexanes showed the reaction was complete.The reaction was diluted to 30 mL with dichloromethane and washed with2N HCl (2×30 mL) and with saturated sodium bicarbonate solution (2×30mL). The organics were isolated, dried (MgSO₄), filtered andconcentrated to a foam, 5-(chloro(4-chloro-3-fluorophenyl)methyl)oxazole(240 mg, 90%). ¹H-NMR shows no mesylate methyl signal. The chloride isthe assumed product.

Step C: NaH (13.2 mg, 0.331 mmol; 60 wt % oil dispersion) neat as asolid was added to a stirred suspension of4-(2-(methylthio)pyrimidin-4-yl)pyridin-2(1H)-one (65.9 mg, 0.301 mmol)in DMF (600 μL) at room temperature under nitrogen. After 30 minutes,the suspension had become a solution. A solution of5-(chloro(4-chloro-3-fluorophenyl)methyl)oxazole (111 mg, 0.451 mmol)was then added as a solution in DMF (300 μL) dropwise by syringe. Afterstirring at room temperature overnight, TLC in ethyl acetate showed anew high rf spot, as well as a new mid rf spot (both bright blue underUV). The reaction was quenched with water (1 mL) and then partitionedbetween ethyl acetate (30 mL) and water with a little brine (30 mL). Theorganics were isolated and washed with water/brine (3×30 mL). Theorganics were isolated, dried (MgSO₄), filtered and concentrated to anoil. The mixture was loaded onto a Biotage 12M column with 7/3 ethylacetate/hexanes and eluted. Two main spots eluted and correspondingfractions were pooled and concentrated. The least polar fraction appearsto be alkylated on the pyridone oxygen. The second eluting spot appearsto be the desired N-alkylated pyridone, which was isolated as a foam,1-((4-chloro-3-fluorophenyl)(oxazol-5-yl)methyl)-4-(2-(methylthio)pyrimidin-4-yl)pyridin-2(1H)-one(50 mg, 39%).

Step D: mCPBA (80.5 mg, 0.350 mmol) neat as a solid was added to astirred solution of1-((4-chloro-3-fluorophenyl)(oxazol-5-yl)methyl)-4-(2-(methylthio)pyrimidin-4-yl)pyridin-2(1H)-one(50 mg, 0.117 mmol) in dichloromethane (2 mL) at room temperature undernitrogen. After 1 hour, TLC in ethyl acetate showed complete consumptionof starting material and a new lower rf spot (bright blue under UVvisualization). The reaction was quenched with 10% Na₂S₂O₃ (1 mL) andstirred for 5 minutes. The reaction was diluted with dichloromethane (20mL) and washed with 10% Na₂S₂O₃ (2×20 mL) and with saturated sodiumbicarbonate solution (2×20 mL). The organics were isolated, dried(MgSO₄), filtered and concentrated to an oil,1-((4-chloro-3-fluorophenyl)(oxazol-5-yl)methyl)-4-(2-(methylsulfonyl)pyrimidin-4-yl)pyridin-2(1H)-one(53 mg, 99%).

Step E: A microwave tube was charged with a solution of1-((4-chloro-3-fluorophenyl)(oxazol-5-yl)methyl)-4-(2-(methylsulfonyl)pyrimidin-4-yl)pyridin-2(1H)-one(53 mg, 0.12 mmol) in DMA (1.2 mL). Tetrahydro-2H-pyran-4-amine (35 mg,0.35 mmol) was added neat by syringe. The reaction was put into amicrowave apparatus and heated to 120° C. After 1 hour, the solution wasdiluted to 30 mL with ethyl acetate and washed with a water/brinemixture (4×30 mL). The organics were isolated, dried (MgSO₄), filteredand concentrated. TLC in ethyl acetate showed complete loss of startingmaterial and a new spot of nearly the same rf. The crude product wasloaded onto a Biotage 12M column with ethyl acetate and eluted. Productcontaining fractions were pooled and concentrated to an oil,1-((4-chloro-3-fluorophenyl)(oxazol-5-yl)methyl)-4-(2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one(20 mg, 36%). ¹H NMR (400 MHz, CDCl₃) δ 8.40 (d, 1H), 7.98 (s, 1H), 7.56(s, 1H), 7.43 (dd, 1H), 7.31 (d, 1H), 7.22 (br s, 1H), 7.08 (s, 1H),7.00 (m, 2H), 6.90 (s, 1H), 6.83 (dd, 1H), 5.20 (br d, 1H), 4.11 (m,1H), 4.01 (m 2H), 355 (m, 2H), 2.06 (m, 2H), 1.58 (m, 2H); m/z(APCI-pos) M+1=483.0.

Example 35

1-((4-chloro-3-fluorophenyl)(1-methyl-1H-pyrazol-4-yl)methyl)-4-(2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one

Step A: Boc₂O (2183 mg, 10.0 mmol) was added to a stirred solution of1H-pyrazole-4-carbaldehyde (961 mg, 10.0 mmol) in acetonitrile (30 mL)at room temperature, followed by 4-dimethylaminopyridine (“DMAP”) (61.1mg, 0.500 mmol). After stirring overnight, the reaction was concentratedto dryness and partitioned between ethyl acetate (30 mL) and water (30mL). The organics were isolated and washed with 0.5N HCL (30 mL) andwith brine (30 mL). The organics were isolated, dried (MgSO₄), filteredand concentrated to an oil, which was loaded onto a Biotage 40M columnwith 4/1 hexanes/ethyl acetate and eluted with the same solvent. Productcontaining fractions were pooled and concentrated to an oil, whicheventually solidified to a solid, tert-butyl4-formyl-1H-pyrazole-1-carboxylate (1.4 g, 71%).

Step B: (4-Chloro-3-fluorophenyl)magnesium bromide (7400 μL, 3.70 mmol)(0.5M in THF) was added dropwise by syringe to a stirred solution oftert-butyl 4-formyl-1H-pyrazole-1-carboxylate (605 mg, 3.08 mmol) in THF(24 mL) at −78° C. under nitrogen. After 10 minutes, TLC in 2/3 ethylacetate/hexanes showed a new spot of lower rf than starting material inan approximate 1:1 ratio. After 1 hour, the reaction was quenched at−78° C. with saturated ammonium chloride solution (10 mL) and allowed towarm to 0° C. The reaction was then partially concentrated to removeTHF, and the residual mixture was partitioned between ethyl acetate (50mL) and water (50 mL). The organics were isolated and washed with brine(30 mL). The organics were again isolated, dried (MgSO₄), filtered andconcentrated. The crude material was loaded onto a Biotage 40S columnwith 35/65 ethyl acetate/hexanes and eluted. Product containingfractions were pooled and concentrated to an oil, tert-butyl4-((4-chloro-3-fluorophenyl)(hydroxy)methyl)-1H-pyrazole-1-carboxylate(400 mg, 40%).

Step C: DIEA (646 μL, 3.71 mmol; d 0.742) neat was added by syringe to astirred solution of tert-butyl4-((4-chloro-3-fluorophenyl)(hydroxy)methyl)-1H-pyrazole-1-carboxylate(808 mg, 2.47 mmol) in dichloromethane (25 mL) at 0° C. under nitrogen,followed by methane sulfonyl chloride (191 μL, 2.47 mmol) neat bysyringe. After 1 hour, TLC in 1/1 ethyl acetate/hexanes showed thereaction was complete with a new high rf spot dominant. The reaction wasdiluted to 50 mL with dichloromethane and washed with 2N HCl (2×50 mL)and with saturated sodium bicarbonate solution (2×50 mL). The organicswere isolated, dried (MgSO₄), filtered and concentrated to a foam,tert-butyl4-(chloro(4-chloro-3-fluorophenyl)methyl)-1H-pyrazole-1-carboxylate (850mg, 100%). The chloride is the assumed product.

Step D: NaH (92.0 mg, 2.30 mmol; 60% oil dispersion) neat as a solid wasadded to a stirred suspension of4-(2-(methylthio)pyrimidin-4-yl)pyridin-2(1H)-one (504 mg, 2.30 mmol) inDMF (15 mL) at room temperature under nitrogen. After 15 minutes, asolution had formed. tert-Butyl4-(chloro(4-chloro-3-fluorophenyl)methyl)-1H-pyrazole-1-carboxylate (794mg, 2.30 mmol) was then added dropwise by syringe as a solution in DMF(7 mL). After stirring overnight, the reaction was quenched by additionof saturated ammonium chloride solution (10 mL). The mixture waspartitioned between ethyl acetate (50 mL) and water (50 mL). Theorganics were isolated and washed with water (3×50 mL) and with brine(50 mL). The organics were isolated, dried (MgSO₄), filtered andconcentrated. The crude product was loaded onto a Biotage 40M columnwith 3/2 ethyl acetate/hexanes and eluted with the same solvent. Productcontaining fractions were pooled and concentrated to a foam, tert-butyl4-((4-chloro-3-fluorophenyl)(4-(2-(methylthio)pyrimidin-4-yl)-2-oxopyridin-1(2H)-yl)methyl)-1H-pyrazole-1-carboxylate(565 mg, 46%).

Step E: Trifluoroacetic acid (“TFA”) (5 mL) was added by pipet to astirred solution of tert-butyl4-((4-chloro-3-fluorophenyl)(4-(2-(methylthio)pyrimidin-4-yl)-2-oxopyridin-1(2H)-yl)methyl)-1H-pyrazole-1-carboxylate(562 mg, 1.06 mmol) in dichloromethane (5 mL) at room temperature undernitrogen. After 3 hours, the reaction was concentrated by rotovap. Theresidue was redissolved in dichloromethane (10 mL), carefully treatedwith saturated sodium bicarbonate solution (10 mL) and stirred rapidlyfor 10 minutes. The layers were separated, and the aqueous phase wasextracted with dichloromethane (20 mL). The combined organics were dried(MgSO₄), filtered and concentrated to a foam,1-((4-chloro-3-fluorophenyl)(1H-pyrazol-4-yl)methyl)-4-(2-(methylthio)pyrimidin-4-yl)pyridin-2(1H)-one(455 mg, 100%).

Step F: NaH (51.0 mg, 1.28 mmol; 60% oil dispersion) neat as a solid wasadded to a stirred solution of1-((4-chloro-3-fluorophenyl)(1H-pyrazol-4-yl)methyl)-4-(2-(methylthio)pyrimidin-4-yl)pyridin-2(1H)-one(455 mg, 1.06 mmol) in DMF (5 mL) at room temperature under nitrogen.After 30 minutes, methyl iodide (86.1 μL, 1.38 mmol) was added neat bysyringe. After stirring overnight, the reaction was quenched by additionof saturated ammonium chloride solution (5 mL). The mixture waspartitioned between ethyl acetate (30 mL) and saturated sodiumbicarbonate (30 mL). The organics were isolated and washed with water(3×30 mL) and with brine (30 mL). TLC in 98/2 ethyl acetate/methanolshowed very little residual starting material with a major new spot ofslightly higher rf. The organics were isolated, dried (MgSO₄), filteredand concentrated. The crude product was loaded onto a Biotage 40S columnwith 98/2 ethyl acetate/methanol and eluted with the same solvent.Product containing fractions were pooled and concentrated to a foam,1-((4-chloro-3-fluorophenyl)(1-methyl-1H-pyrazol-4-yl)methyl)-4-(2-(methylthio)pyrimidin-4-yl)pyridin-2(1H)-one(340 mg, 72%).

Step G: mCPBA (523 mg, 2.27 mmol) neat as a solid was added to a stirredsolution of1-((4-chloro-3-fluorophenyl)(1-methyl-1H-pyrazol-4-yl)methyl)-4-(2-(methylthio)pyrimidin-4-yl)pyridin-2(1H)-one(335 mg, 0.758 mmol) in dichloromethane (7.6 mL) at room temperatureunder nitrogen. After 1 hour, TLC in ethyl acetate showed completeconsumption of starting material and a new lower rf spot (bright blueunder UV visualization). The reaction was quenched with 10% Na₂S₂O₃ (10mL) and stirred for 5 minutes. The reaction was diluted withdichloromethane (40 mL) and washed with 10% Na₂S₂CO₃ (2×50 mL) andsaturated sodium bicarbonate solution (2×50 mL). The organics wereisolated, dried (MgSO₄), filtered and concentrated to an oil,1-((4-chloro-3-fluorophenyl)(1-methyl-1H-pyrazol-4-yl)methyl)-4-(2-(methylsulfonyl)pyrimidin-4-yl)pyridin-2(1H)-one(343 mg, 95%).

Step H:1-((4-Chloro-3-fluorophenyl)(1-methyl-1H-pyrazol-4-yl)methyl)-4-(2-(methylsulfonyl)pyrimidin-4-yl)pyridin-2(1H)-one(343 mg, 0.724 mmol) as a solution in DMA (5 mL) was added to amicrowave tube equipped with a stir bar. Tetrahydro-2H-pyran-4-amine(366 mg, 3.62 mmol) was then added neat by syringe. The solution washeated in a microwave apparatus with stirring to 120° C. for 1 hour.After 1 hour, the solution was diluted to 30 mL with ethyl acetate andwashed with a water/brine mixture (4×30 mL). The organics were isolated,dried (MgSO₄), filtered and concentrated. TLC in 5/95 methanol/ethylacetate showed complete loss of starting material and a new spot ofnearly the same rf. The crude product was loaded onto a Biotage 40Scolumn with 2.5/97.5 methanol/ethyl acetate and eluted. Productcontaining fractions were pooled and concentrated to a foam,1-((4-chloro-3-fluorophenyl)(1-methyl-1H-pyrazol-4-yl)methyl)-4-(2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one(225 mg, 63%). ¹H NMR (400 MHz, CDCl₃) δ 8.39 (d, 1H), 7.37 (m, 4H),7.23 (s, 1H), 7.18 (br s, 1H), 7.00 (m, 2H), 6.90 (d, 1H), 6.79 (dd,1H), 5.15 (br d, 1H), 4.11 (m, 1H), 4.00 (m, 2H), 3.91 (s, 3H), 3.56 (m,2H), 2.06 (m, 2H), 1.57 (m, 2H); m/z (APCI-pos) M+1=496.1.

Example 36

1-((4-chloro-3-fluorophenyl)(1-methyl-1H-pyrazol-4-yl)methyl)-4-(5-fluoro-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one

Step A: NaH (8.1 mg, 0.20 mmol; 60% oil dispersion) neat as a solid wasadded to a stirred suspension of4-(5-fluoro-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one(59 mg, 0.20 mmol) in DMF (1.5 mL) at room temperature under nitrogen.After 15 minutes, a solution had formed. tert-Butyl4-(chloro(4-chloro-3-fluorophenyl)methyl)-1H-pyrazole-1-carboxylate (70mg, 0.20 mmol) was then added dropwise by syringe as a solution in DMF(500 μL). After stirring overnight, the reaction was quenched byaddition of saturated ammonium chloride solution (1 mL). The mixture waspartitioned between ethyl acetate (30 mL) and water (30 mL). Theorganics were isolated and washed with water (3×30 mL) and with brine(30 mL). The organics were isolated, dried (MgSO₄), filtered andconcentrated. The crude product was dissolved in a minimum ofdichloromethane and filtered to remove insoluble unreacted pyridone. Thefiltrate was re-concentrated and loaded onto a Biotage 12M column with1/1 ethyl acetate/hexanes and eluted. Product containing fractions werepooled and concentrated to a foam, tert-butyl4-((4-chloro-3-fluorophenyl)(4-(5-fluoro-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-2-oxopyridin-1(2H)-yl)methyl)-1H-pyrazole-1-carboxylate(46 mg, 38%).

Step B: TFA (1 mL) was added to a stirred solution of tert-butyl4-((4-chloro-3-fluorophenyl)(4-(5-fluoro-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-2-oxopyridin-1(2H)-yl)methyl)-1H-pyrazole-1-carboxylate(46 mg, 0.077 mmol) in dichloromethane (1 mL) at room temperature undera nitrogen balloon. After 3 hours, the reaction was concentrated byrotovap. The residue was redissolved in dichloromethane (10 mL) andcarefully treated with saturated sodium bicarbonate solution (10 mL) andstirred rapidly for 10 minutes. The layers were separated, and theaqueous phase was extracted with dichloromethane (10 mL). The combinedorganics were dried (MgSO₄), filtered and concentrated to a foam,1-((4-chloro-3-fluorophenyl)(1H-pyrazol-4-yl)methyl)-4-(5-fluoro-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one(38 mg, 100%).

Step C: NaH (3.05 mg, 0.0762 mmol; 60% oil dispersion) neat as a solidwas added to a stirred solution of1-((4-chloro-3-fluorophenyl)(1H-pyrazol-4-yl)methyl)-4-(5-fluoro-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one(38 mg, 0.0762 mmol) in DMF (1 mL) at room temperature under nitrogen.After 15 minutes, a red solution had formed. Methyl iodide (4.75 μL,0.0762 mmol) was then added neat by syringe. After stirring overnight,the reaction was quenched by addition of saturated ammonium chloridesolution (1 mL). The mixture was partitioned between ethyl acetate (15mL) and saturated sodium bicarbonate (15 mL). The organics were isolatedand washed with water (3×15 mL) and with brine (15 mL). TLC in 95/5ethyl acetate/methanol showed complete consumption of starting materialwith two new major spots of higher rf. The organics were isolated, dried(MgSO₄), filtered and concentrated. The crude product was loaded onto a20 cm×20 cm×0.5 mm prep plate and eluted with 95/5 ethylacetate/methanol. Three bands were scraped off the plate. Compound wasfreed from the silica gel by stirring for 15 minutes with ethyl acetate(50 mL) and filtration. The high rf material shows two methyl signals by¹H-NMR and is presumed to be dimethylated byproduct. The lower rfmaterial was isolated as a clear oil,1-((4-chloro-3-fluorophenyl)(1-methyl-1H-pyrazol-4-yl)methyl)-4-(5-fluoro-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one(9 mg, 23%) and appears to be the desired product by comparison to thenon-fluoro analog (see Example 35). ¹H NMR (400 MHz, CDCl₃) δ 8.27 (d,1H), 7.36 (m, 3H), 7.30 (br s, 1H), 7.23 (s, 1H), 7.01 (m, 2H), 6.80 (d,1H), 5.09 (d, 1H), 4.00 (m, 3H), 3.91 (s, 3H), 3.54 (m, 2H), 2.04 (m,2H), 1.57 (m, 2H).

Example 37

1-(4-chloro-3-fluorophenethyl)-4-(2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one

Step A: DIEA (172 μL, 0.985 mmol; d 0.742) neat was added by syringe toa stirred solution of 2-(4-chloro-3-fluorophenyl)ethanol (172 mg, 0.985mmol) in dichloromethane (3 mL) at 0° C. under nitrogen, followed bymethanesulfonyl chloride (76.2 μL, 0.985 mmol) neat by syringe. After 15minutes, TLC in 1/1 ethyl acetate/hexanes showed a new high rf spot.Starting material was completely consumed. The reaction was diluted to30 mL with dichloromethane and washed with 2N HCl (2×30 mL) and withsaturated sodium bicarbonate solution (2×30 mL). The organics wereisolated, dried (MgSO₄), filtered and concentrated to an oil,4-chloro-3-fluorophenethyl methanesulfonate (240 mg, 96%).

Step B: NaH (11.1 mg, 0.277 mmol; 60% oil dispersion) neat as a solidwas added to a stirred suspension of4-(2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one(75.4 mg, 0.277 mmol) in DMF (700 μL) at room temperature undernitrogen. After 15 minutes, a clear solution had formed. A solution of4-chloro-3-fluorophenethyl methanesulfonate (105 mg, 0.416 mmol) in ofDMF (700 μL) was then added dropwise. After stirring overnight, thereaction was quenched by addition of saturated ammonium chloridesolution (1 mL). The mixture was partitioned between ethyl acetate (30mL) and water (30 mL). The organics were isolated and washed with water(3×30 mL) and with brine (30 mL). The organics were isolated, dried(MgSO₄), filtered and concentrated. The crude product was loaded onto aBiotage 12M column with 2.5/97.5 methanol/ethyl acetate and eluted. Theundesired O-alkylated product eluted first and was not collected.Product containing fractions then eluted and were pooled andconcentrated to an oil that eventually solidified,1-(4-chloro-3-fluorophenethyl)-4-(2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one(20 mg, 17%). ¹H NMR (400 MHz, CDCl₃) δ 8.38 (d, 1H), 7.30 (dd, 1H),7.18 (br s, 1H), 7.02 (d, 1H), 6.98 (dd, 1H), 6.90 (m, 2H), 6.66 (dd,1H), 5.17 (br d, 1H), 4.16 (t, 2H), 4.12 (m, 1H), 4.00 (m, 2H), 3.57 (m,2H), 3.08 (t, 2H), 2.06 (m, 2H), 1.58 (m, 2H); m/z (APCI-pos) M+1=430.1.

Example 38

(R)-1-(1-(4-chloro-3-fluorophenyl)-3-hydroxypropyl)-4-(2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one

Step A: Potassium bis(trimethylsilyl)amide (0.91M in THF, 0.202 mL) wasadded to a cooled to 0° C. suspension of4-(2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one(40 mg, 0.147 mmol) in 2-methyltetrahydrofuran (4 mL). The mixture wasagitated 15 minutes, and(S)-3-(tert-butyldimethylsilyloxy)-1-(4-chloro-3-fluorophenyl)propylmethanesulfonate (81.6 mg, 0.206 mmol) in 2-methyltetrahydrofuran (1 mL)was added. The mixture was then heated to 75° C. and agitated overnight.The reaction was quenched with saturated sodium bicarbonate solution anddiluted with ethyl acetate (5 mL). The organic layer was washed withwater (2×) and evaporated. Purified by chromatography on silica gel,eluted with 50-75% ethyl acetate/hexanes to give(R)-1-(3-(tert-butyldimethylsilyloxy)-1-(4-chloro-3-fluorophenyl)propyl)-4-(2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one(0.056 g, 0.0977 mmol, 66.5% yield) as thick oil.

Step B:(R)-1-(3-(tert-Butyldimethylsilyloxy)-1-(4-chloro-3-fluorophenyl)propyl)-4-(2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one(0.056 g, 0.098 mmol) was dissolved in chloroform (1 mL), and 4M HCl indioxane was added. After agitating for 30 minutes, the mixture wasevaporated and dried in vacuo to give(R)-1-(1-(4-chloro-3-fluorophenyl)-3-hydroxypropyl)-4-(2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one(0.045 g, 0.098 mmol, quantitative yield) as a solid. ¹H NMR (400 MHz,CDCl₃) δ 9.22 (d, J=5.0 Hz, 1H), 8.37 (d, J=5.0 Hz, 1H), 7.42 (t, J=5.0Hz, 1H), 7.36 (s, 1H), 7.28-7.10 (m, 4H), 6.77 (d, J=5.0 Hz, 1H), 6.45(m, 1H), 4.25 (br s, 1H), 4.20-4.00 (m, 2H), 3.80-3.42 (m, 9H), 2.55 (m,1H), 2.20 (m, 1H), 2.02 (m, 2H), 1.82 (m, 2H); m/z (APCI-pos) M+1=459.0.

Example 39

(S)-1-(1-(4-chloro-3-fluorophenyl)-2-hydroxyethyl)-4-(2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one

Step A:(S)-1-(2-(tert-Butyldimethylsiloxy)-1-(4-chloro-3-fluorophenyl)ethyl)-4-(2-(methylsulfonyl)pyrimidin-4-yl)pyridine-2(1H)-one(47 mg, 0.087 mmol), 2-methyl pyrazole-3-amine (0.175 mmol, 2.0equivalents) and anhydrous DMF (3.0 mL) were added to a 25 mL roundbottomed flask equipped with a stirring bar. The flask was capped with arubber septum and flushed with nitrogen. Under a blanket of nitrogen,sodium hydride (8.5 mg, 60% dispersion in mineral oil) was added in oneportion. The flask was flushed with nitrogen, capped and stirred at roomtemperature. The reaction progress was monitored by LCMS, and after 30minutes, the starting material was consumed. The reaction mixture wasquenched by the addition of water (0.5 mL) and ethyl acetate (15 mL).The contents of the round bottomed flask were transferred to a 125 mLseparatory funnel, and the reaction flask was rinsed several times withadditional ethyl acetate. Crude(S)-1-(2-((tert-butyldimethylsilyl)oxy)-1-(4-chloro-3-fluorophenyl)ethyl)-4-(2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-onewas partitioned between ethyl acetate and water (80 mL/30 mL). The ethylacetate layer was washed once with brine, dried (MgSO₄), filtered andconcentrated to give crude(S)-1-(2-((tert-butyldimethylsilyl)oxy)-1-(4-chloro-3-fluorophenyl)ethyl)-4-(2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one.The crude was taken directly into the deprotection step.

Step B: Crude(S)-1-(2-((tert-butyldimethylsilyl)oxy)-1-(4-chloro-3-fluorophenyl)ethyl)-4-(2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one(48 mg) was dissolved in ethyl acetate (4 mL) and treated dropwiseslowly (over 2 minutes) with an ethyl acetate solution (1.0 mL, whichhad been saturated with HCl gas). The reaction stirred at roomtemperature for 15 minutes, after which time LCMS indicated completeconsumption of the starting material. The reaction mixture wasconcentrated to an oily residue and purified by prep RP HPLC to yield(S)-1-(1-(4-chloro-3-fluorophenyl)-2-hydroxyethyl)-4-(2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one(20.8 mg, 54.6% yield) as a lyophilized powder. ¹H NMR (400 MHz,(CD₃)₂SO) δ 9.58 (s, 1H), 8.60 (d, J=5.1 Hz, 1H), 7.91 (t, J=9.0 Hz,1H), 7.58 (t, J=8.1 Hz, 1H), 7.52-7.41 (m, 2H), 7.37 (d, J=1.8 Hz, 1H),7.14 (dd, J=10.7, 5.1 Hz 2H), 6.86 (dd, J=7.3, 1.8 Hz, 1H), 6.27 (d,J=1.7 Hz, 1H), 5.97 (dd, J=7.7, 5.7 Hz, 1H), 5.31 (t, J=5.2 Hz, 1H),4.15 (m, 1H), 4.10-3.95 (m, 1H), 3.69 (s, 3H); LCMS m/z 441 (M+H)+.

Example 40

1-((1H-indol-6-yl)methyl)-4-(2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one

Step A: N,N-Dimethylpyridin-4-amine (460 mg, 3.76 mmol) anddi-tert-butyl dicarbonate (6.17 g, 28.3 mmol) were added to a solutionof methyl 1H-indole-1,6-dicarboxylate (3.30 g, 18.8 mmol) inacetonitrile (60 mL) at room temperature. The reaction mixture wasstirred at room temperature overnight. After removal of the solvent, theresidue was purified by silica gel chromatography, eluting withpetroleum ether/ethyl acetate (10:1) to afford 1-tert-butyl 6-methyl1H-indole-1,6-dicarboxylate (4.9 g, 95% yield) as a solid. LCMS (ESI)m/z 220.1 [M+H-56]⁺, 276.1 [M+H]⁺.

Step B: Diisobutylaluminum hydride (1M in toluene, 12 mL, 12 mmol) wasadded to a solution of 1-tert-butyl 6-methyl 1H-indole-1,6-dicarboxylate(1.38 g, 5.00 mmol) in toluene (15 mL) at −50° C. over 10 minutes. Afterbeing stirred at −50° C. for 30 minutes, the reaction was quenched withmethanol (2.5 mL) and water (2.5 mL). The resulting precipitate wasfiltered off, and the filtrate was evaporated. The residue was purifiedby silica gel chromatography, eluting with petroleum ether/ethyl acetate(5:1 to 1:1) to afford tert-butyl6-(hydroxymethyl)-1H-indole-1-carboxylate (815 mg, 55% yield) as an oil.LCMS (ESI) m/z 174.3 [M+H-18-56]⁺, 230.3 [M+H-18]⁺.

Step C: Triethylamine (122 mg, 1.20 mmol) and methanesulfonyl chloride(138 mg, 1.20 mmol) were added to a solution of tert-butyl6-(hydroxymethyl)-1H-indole-1-carboxylate (198 mg, 0.800 mmol) indichloromethane (10 mL) at room temperature. The reaction mixture wasstirred at room temperature overnight. After being diluted withdichloromethane (15 mL), the mixture was washed with water (15 mL),dried with anhydrous Na₂SO₄, and filtered. After removal of the solvent,the residue (tert-butyl6-((methylsulfonyloxy)methyl)-1H-indole-1-carboxylate) was used directlyin the next step.

Step D: KOt-Bu (180 mg, 1.6 mmol) and n-Bu₄NI (37 mg, 0.1 mmol) wereadded to a mixture of tert-butyl6-((methylsulfonyloxy)methyl)-1H-indole-1-carboxylate (0.8 mmol) and4-(2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one(164 mg, 0.6 mmol) in anhydrous THF (15 mL). The resulting mixture wasstirred at 70° C. under microwave irradiation for 2 hours. LC-MS showedthe tert-butyl 6-(((methylsulfonyl)oxy)methyl)-1H-indole-1-carboxylatehad disappeared. The reaction mixture was treated with water (20 mL) anddiluted with dichloromethane. After removal of the insolubles byfiltration, the filtrate was extracted with dichloromethane. Thecombined organic phase was dried with Na₂SO₄ and concentrated. Theresidue was purified with Combiflash (A: H₂O including 0.5% NH₃HCO₃, B:CH₃CN) to afford tert-butyl6-((2-oxo-4-(2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)pyridin-1(2H)-yl)methyl)-1H-indole-1-carboxylate(70 mg, 23% yield).

Step E: TFA (2 mL) was added to a solution of tert-butyl6-((2-oxo-4-(2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)pyridin-1(2H)-yl)methyl)-1H-indole-1-carboxylate (70 mg, 0.14 mmol) indichloromethane (3 mL) at 20° C. The mixture was stirred at roomtemperature for 2 hours. LC-MS showed the tert-butyl6-((2-oxo-4-(2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)pyridin-1(2H)-yl)methyl)-1H-indole-1-carboxylatehad disappeared. The reaction mixture was adjusted with a saturatedNaHCO₃ solution to a pH of around 8-9, then extracted withdichloromethane, and dried with Na₂SO₄. The organic phase wasevaporated, and the residue was purified with prep-HPLC (A: H₂Oincluding 0.5% NH₃HCO₃, B: CH₃CN) to afford1-((1H-indol-6-yl)methyl)-4-(2-(tetrahydro-2H-pyran-4-ylamino)pyrimidin-4-yl)pyridin-2(1H)-one(11 mg, 20% yield). ¹H NMR (500 MHz, (CD₃)₂SO) δ 11.10 (s, 1H), 8.41 (d,J=5.0 Hz, 1H), 7.92 (d, J=7.0 Hz, 1H), 7.50 (d, J=8 Hz, 1H), 7.40-7.32(m, 3H), 7.15-7.11 (m, 2H), 7.03 (d, J=8 Hz, 1H), 6.85 (d, J=7 Hz, 1H),6.39 (s, 1H), 5.22 (s, 2H), 3.98 (m, 1H), 3.89-3.85 (m, 2H), 3.45-3.36(m, 2H), 1.86-1.83 (m, 2H), 1.60-1.45 (m, 2H); LCMS (ESI) m/z: 402.2[M+H+].

Example 41

1-((1H-indol-2-yl)methyl)-4-(2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one

Step A: N,N-Dimethylpyridin-4-amine (460 mg, 3.76 mmol) anddi-tert-butyl dicarbonate (4.46 g, 40 mmol) were added to a solution ofmethyl 1H-indole-1,6-dicarboxylate (3.5 g, 20.0 mmol) in acetonitrile(60 mL) at room temperature. The reaction mixture was stirred at roomtemperature overnight. After removal of the solvent, the residue waspurified by silica gel chromatography, eluting with petroleumether/ethyl acetate (10:1) to afford 1-tert-butyl 2-methyl1H-indole-1,6-dicarboxylate (5.1 g, 92% yield) as a solid.

Step B: Diisobutylaluminum hydride (1M in toluene, 29 mL, 29 mmol) wasadded to a solution of 1-tert-butyl 2-methyl 1H-indole-1,6-dicarboxylate(3.28 g, 12.0 mmol) in toluene (25 mL) at −50° C. over 10 minutes. Afterbeing stirred at −50° C. for 30 minutes, the reaction was quenched withmethanol (10 mL) and water (10 mL). The resulting precipitate wasfiltered off, and the filtrate was evaporated. The residue was purifiedby silica gel chromatography, eluting with petroleum ether/ethyl acetate(5:1 to 1:1) to afford tert-butyl2-(hydroxymethyl)-1H-indole-1-carboxylate (1.5 g, 51% yield) as an oil.LCMS (ESI) m/z 174.3 [M+H-18-56]⁺.

Step C: Triethylamine (194 mg, 1.7 mmol) and methanesulfonyl chloride(171 mg, 1.7 mmol) were added to a solution of tert-butyl2-(hydroxymethyl)-1H-indole-1-carboxylate (300 mg, 1.20 mmol) indichloromethane (10 mL) at room temperature. The reaction mixture wasstirred at room temperature overnight. After being diluted withdichloromethane (15 mL), the mixture was washed with water (15 mL),dried over anhydrous Na₂SO₄, and filtered. After removal of the solvent,the residue (tert-butyl2-((methylsulfonyloxy)methyl)-1H-indole-1-carboxylate) was used directlyin the next step.

Step D: KOt-Bu (224 mg, 2 mmol) and n-Bu₄NI (37 mg, 0.1 mmol) were addedto a mixture of tert-butyl2-((methylsulfonyloxy)methyl)-1H-indole-1-carboxylate (350 mg, 1.07mmol) and4-(2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one(272 mg, 1 mmol) in anhydrous THF (15 mL). The resulting mixture wasstirred at 70° C. under microwave irradiation for 2 hours. LC-MS showedthe tert-butyl 2-(((methylsulfonyl)oxy)methyl)-1H-indole-1-carboxylatehad disappeared. The reaction mixture was treated with water (20 mL) anddiluted with dichloromethane. After removal of the insolubles byfiltration, the filtrate was extracted with dichloromethane. Thecombined organic phase was dried with Na₂SO₄ and concentrated. Theresidue was purified with Combiflash (A: H₂O including 0.5% NH₃HCO₃, B:CH₃CN) to afford tert-butyl2-((2-oxo-4-(2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)pyridin-1(2H)-yl)methyl)-1H-indole-1-carboxylate(130 mg, 26% yield).

Step E: TFA (2 mL) was added to a solution of tert-butyl2-((2-oxo-4-(2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)pyridin-1(2H)-yl)methyl)-1H-indole-1-carboxylate (130 mg, 0.32 mmol) indichloromethane (3 mL) at 20° C. The mixture was stirred at roomtemperature for 2 hours. LC-MS showed the tert-butyl2-((2-oxo-4-(2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)pyridin-1(2H)-yl)methyl)-1H-indole-1-carboxylatehad disappeared. The reaction mixture was adjusted to a pH of around 8-9with saturated NaHCO₃ solution, extracted with dichloromethane, anddried with Na₂SO₄. The organic phase was evaporated, and the residue waspurified with prep-HPLC (A: H₂O including 0.5% NH₃HCO₃, B: CH₃CN) toafford1-((1H-indol-2-yl)methyl)-4-(2-(tetrahydro-2H-pyran-4-ylamino)pyrimidin-4-yl)pyridin-2(1H)-one(60 mg, 60% yield). ¹H NMR (500 MHz, (CD₃)₂SO) δ 11.07 (s, 1H), 8.41 (d,J=4.5 Hz, 1H), 7.88 (d, J=7.5 Hz, 1H), 7.47 (d, J=8 Hz, 1H), 7.37-7.36(m, 2H), 7.15-7.14 (m, 2H), 7.06 (m 1H), 6.96 (m, 1H), 6.88 (d, J=6 Hz,1H), 6.35 (s, 1H), 5.26 (s, 2H), 3.97 (m, 1H), 3.88-3.86 (m, 2H),3.42-3.37 (m, 2H), 1.85-1.83 (m, 2H), 1.56-1.48 (m, 2H); LCMS (ESI) m/z402.3 [M+H+].

Example 42

4-(2-((1S,4R,5R)-2-oxabicyclo[2.2.1]heptan-5-ylamino)pyrimidin-4-yl)-1-((S)-1-(4-chloro-3-fluorophenyl)-2-hydroxyethyl)pyridin-2(1H)-one

Step A: Diphenylphosphoryl azide (“DPPA”) (0.97 g, 3.5 mmol) andtriethylamine (384 mg, 3.80 mmol) were added to a solution of3-oxo-2-oxa-bicyclo[2.2.1]heptane-5-carboxylic acid (0.50 g, 3.2 mmol;prepared according to WO 2008/092955) in dry toluene (5.0 mL). Theresulting mixture was stirred at 100° C. under nitrogen atmosphere.After adding phenylmethanol (354 mg, 3.50 mmol), the mixture was stirredat 130° C. for another 2 hours. After being quenched with water (1 mL),the mixture was diluted with ethyl acetate (300 mL), washed withsaturated brine (3×50 mL), dried over anhydrous sodium sulfate, and thenconcentrated. The residue was purified by silica gel chromatographyeluting with petroleum ether/ethyl acetate (4:1) to give benzyl3-oxo-2-oxa-bicyclo[2.2.1]heptan-5-ylcarbamate (600 mg, 72% yield) as asolid. ¹H NMR (500 MHz, CDCl₃) δ 7.80-7.74 (m, 1H), 7.39-7.31 (m, 5H),5.08-5.00 (m, 3H), 3.87 (s, 1H), 2.78 (s, 1H), 2.24-2.15 (m, 1H), 2.14(d, J=9.0 Hz, 1H), 1.97 (t, J=20.5 Hz, 1H), 1.71 (d, J=14.0 Hz, 1H).

Step B: NaBH₄ (0.580 g, 15.2 mmol) was added to a solution of benzyl3-oxo-2-oxa-bicyclo[2.2.1]heptan-5-ylcarbamate (1.0 g, 3.8 mmol) andCaCl₂ (0.85 g, 7.6 mmol) in ethanol (50 mL) at 0° C. After being stirredat room temperature for 12 hours, the reaction mixture was treated withconcentrated HCl. The volatiles were removed, and the residue wasextracted with CHCl₃ (3×100 mL), washed with water (50 mL) and brine (50mL), dried over anhydrous sodium sulfate and concentrated. The residuewas re-crystallized from petroleum ether to afford benzyl4-hydroxy-2-(hydroxymethyl)cyclopentylcarbamate (750 mg, 75% yield) as asolid. ¹H NMR (500 MHz, (CD₃)₂SO) δ 7.38-7.31 (m, 5H), 7.25 (d, J=13.5Hz, 1H), 4.99 (s, 2H), 4.53 (d, J=4 Hz, 1H), 4.48 (t, J=10 Hz, 1H), 4.09(d, J=4 Hz, 1H), 3.73 (t, J=15.5 Hz, 1H), 3.46-3.43 (m, 1H), 3.31-3.28(m, 1H), 1.99 (d, J=7 Hz, 1H), 1.80-1.74 (m, 2H), 1.57 (t, J=12.5 Hz,1H), 1.26 (s, 1H).

Step C: A solution of TsCl (290 mg, 1.52 mmol) in dry toluene (3.0 mL)was added dropwise to a solution of benzyl4-hydroxy-2-(hydroxymethyl)cyclopentylcarbamate (100 mg, 0.380 mmol) anddry pyridine (3.0 mL) in dry toluene (6.0 mL) at 0° C. The mixture wasthen warmed to room temperature and stirred for 2 days. The reactionmixture was heated to 120° C. and stirred for another 16 hours. Afterconcentration, the residue was purified by reverse phase Combi-flash(0.3% NH₄HCO₃/CH₃CN) to afford benzyl2-oxa-bicyclo[2.2.1]heptan-5-ylcarbamate as a solid (58 mg, 62% yield).¹H NMR (500 MHz, CD₃OD) δ 7.37-7.31 (m, 5H), 5.09 (s, 2H), 4.33 (s, 1H),3.73 (d, J=5.5 Hz, 1H), 3.63-3.61 (m, 1H), 3.48 (d, J=7.5 Hz, 1H), 2.53(s, 1H), 2.07-2.04 (m, 1H), 1.72 (d, J=10.5 Hz, 1H), 1.61 (d, J=11.0 Hz,1H), 1.42 (d, J=14.0 Hz, 1H).

Step D: A mixture of benzyl 2-oxa-bicyclo[2.2.1]heptan-5-ylcarbamate(0.50 g, 2.0 mmol) and Pd/C (10%, 50 mg) in methanol (20 mL) was stirredunder hydrogen atmosphere (1 atm) at room temperature for 16 hours.After completion of the reaction, the reaction mixture was adjusted topH around 4 by 1M HCl in methanol. The mixture was filtered throughCelite® and concentrated under reduced pressure to give2-oxa-bicyclo[2.2.1]heptan-5-amine hydrochloride (300 mg, 100% yield) asa solid. ¹H NMR (500 MHz, CD₃OD) δ 4.43 (s, 1H), 3.72-3.70 (m, 1H), 3.54(d, J=7.5 Hz, 1H), 3.50-3.48 (m, 1H), 2.76 (s, 1H), 2.20-2.15 (m, 1H),1.96 (d, J=11.0 Hz, 1H), 1.78 (d, J=11.0 Hz, 1H), 1.61 (d, J=11.0 Hz,1H).

Step E: A microwave vial was charged with(S)-1-(2-(tert-butyldimethylsilyloxy)-1-(4-chloro-3-fluorophenyl)ethyl)-4-(2-(methylsulfonyl)pyrimidin-4-yl)pyridin-2(1H)-one(100 mg, 0.190 mmol), 2-oxa-bicyclo[2.2.1]heptan-5-amine hydrochloride(53 mg, 0.47 mmol), TEA (0.50 mmol, 50 mg) and s-butanol (3.0 mL). Themixture was stirred at 130° C. under microwave irradiation for 3 hours.After completion of the reaction, the mixture was concentrated to give4-(2-(2-oxabicyclo[2.2.1]heptan-5-ylamino)pyrimidin-4-yl)-1-((S)-2-(tert-butyldimethylsilyloxy)-1-(4-chloro-3-fluorophenyl)ethyl)pyridin-2(1H)-oneas an oil, which was used in the next step without further purification.LCMS (ESI) m/z: 571.3 [M+H]+.

Step F: The crude4-(2-(2-oxabicyclo[2.2.1]heptan-5-ylamino)pyrimidin-4-yl)-1-((S)-2-(tert-butyldimethylsilyloxy)-1-(4-chloro-3-fluorophenyl)ethyl)pyridin-2(1H)-onewas dissolved in a solution of HCl in methanol (5 mL, 1M). After beingstirred at room temperature for 2 hours, the reaction mixture was thenadjusted to pH around 8 by saturated Na₂CO₃. The resulting mixture wasextracted with ethyl acetate (3×20 mL). The combined organic layers weredried over Na₂SO₄ and concentrated. The residue was purified byprep-HPLC to afford4-(2-(2-oxabicyclo[2.2.1]heptan-5-ylamino)pyrimidin-4-yl)-1-((S)-1-(4-chloro-3-fluorophenyl)-2-hydroxyethyl)pyridin-2(1H)-one(23 mg, 29% yield). ¹H NMR (500 MHz, CD₃OD) δ 8.42 (d, J=5.0 Hz, 1H),7.86 (d, J=8.5 Hz, 1H), 7.51 (t, J=16 Hz, 1H), 7.35-07.33 (m, 1H), 7.29(s, 1H), 7.20 (d, J=8.0 Hz, 1H), 7.14 (d, J=5.5 Hz, 1H), 7.08-7.06 (m,1H), 6.15-6.13 (m, 1H), 4.40 (s, 1H), 4.32-4.28 (m, 1H), 4.22-4.19 (m,1H), 4.09-4.07 (m, 1H), 3.71-3.69 (m, 1H), 3.61 (d, J=7.0 Hz, 1H), 2.69(s, 1H), 2.19 (t, J=12.0 Hz, 1H), 1.86 (d, J=10.5 Hz, 1H), 1.66 (d,J=10.0 Hz, 1H), 1.58 (d, J=14.0 Hz, 1H); LCMS (ESI) m/z: 571.3 [M+H]+.

Example 43

1-(1-(4-chloro-3-fluorophenyl)-3-hydroxybutyl)-4-(2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one

Step A: Proline (23 mg, 0.20 mmol) was added to a solution of4-chloro-3-fluorobenzaldehyde (159 mg, 1.00 mmol) in acetone (2.5 mL).The resulting mixture was stirred at room temperature overnight. Thereaction mixture was then treated with saturated ammonium chloride.After partitioning, the aqueous layer was extracted with ethyl acetate(3×25 mL). The combined organic layers were dried over anhydrous Na₂SO₄and concentrated. The residue was purified by silica gel columnchromatography eluting with ethyl acetate/petroleum ether (1:4) toafford 4-(4-chloro-3-fluorophenyl)-4-hydroxybutan-2-one (160 mg, 73%yield) as a solid. ¹H NMR (500 MHz, CDCl₃) δ 7.36 (m, 1H), 7.19 (m, 1H),7.06 (m, 1H), 5.13 (t, J=6.5 Hz, 1H), 3.43 (br s, 1H), 2.82 (d, J=6.5Hz, 1H), 2.21 (s, 3H).

Step B: Sodium borohydride (112 mg, 2.95 mmol) was added in threeportions to a solution of4-(4-chloro-3-fluorophenyl)-4-hydroxybutan-2-one (160 mg, 0.73 mmol) inmethanol (5 mL). The resulting mixture was stirred at room temperatureovernight. The reaction mixture was then treated with saturated ammoniumchloride. After removal of methanol, the aqueous layer was extractedwith ethyl acetate (3×25 mL). The combined organic layers were dried andconcentrated to give 1-(4-chloro-3-fluorophenyl)butane-1,3-diol (130 mg,81% yield) as a solid. ¹H NMR (500 MHz, CDCl₃) δ 7.36 (m, 1H), 7.17 (m,1H), 7.04 (m, 1H), 5.07 (m, 1H), 3.48 (br s, 1H), 2.13 (m, 1H), 1.56 (m,1H), 1.30 (d, J=6.0 Hz, 3H).

Step C: Imidazole (96.0 mg, 1.42 mmol) andtert-butylchlorodimethylsilane (107 mg, 0.710 mmol) were added to asolution of 1-(4-chloro-3-fluorophenyl)butane-1,3-diol (130 mg, 0.590mmol) in DCM (10 mL). The resulting mixture was stirred at roomtemperature overnight. The reaction mixture was then diluted with DCM(15 mL), washed with brine and water, dried over anhydrous Na₂SO₄, andconcentrated. The residue was purified by silica gel columnchromatography eluting with ethyl acetate/petroleum ether (1:4) toafford3-(tert-butyldimethylsilyloxy)-1-(4-chloro-3-fluorophenyl)butan-1-ol(130 mg, 66% yield) as oil.

Step D: Triethylamine (84 mg, 0.85 mmol) and methanesulfonyl chloride(94.6 mg, 0.850 mmol) were added at room temperature to a solution of3-(tert-butyldimethylsilyloxy)-1-(4-chloro-3-fluorophenyl)butan-1-ol(250 mg, 0.75 mmol) in DCM (15 mL). After being stirred at roomtemperature overnight, the reaction mixture was diluted withdichloromethane (15 mL), washed with water (15 mL), dried over anhydrousNa₂SO₄, and concentrated. The product,3-(tert-butyldimethylsilyloxy)-1-(4-chloro-3-fluorophenyl)butylmethanesulfonate, was used directly in the next step.

Step E: Potassium 2-methylpropan-2-olate (135 mg, 1.20 mmol),tetrabutylammonium iodide (67 mg, 0.18 mmol), and a solution of3-(tert-butyldimethylsilyloxy)-1-(4-chloro-3-fluorophenyl)butylmethanesulfonate (0.75 mmol) in anhydrous THF (15 mL) were added to asuspension of4-(2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one(163 mg, 0.600 mmol) in anhydrous THF (5.0 mL). The resulting mixturewas stirred at 95° C. under microwave irradiation for 2 hours. Thereaction was quenched with water (20 mL). The mixture was furtherdiluted with DCM. After removal of the insoluble by filtration, thefiltrate was extracted with DCM. The combined organic phases were driedover Na₂SO₄ and concentrated. The residue was purified by Combiflash(0.5% NH₃HCO₃/CH₃CN) to afford1-(3-(tert-butyldimethylsilyloxy)-1-(4-chloro-3-fluorophenyl)butyl)-4-(2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one(80 mg, 26% yield). LCMS (ESI) m/z: 587.2 [M+H]⁺.

Step F: HCl/methanol (3N, 1.0 mL) was added at 5° C. to a solution of1-(3-(tert-butyldimethylsilyloxy)-1-(4-chloro-3-fluorophenyl)butyl)-4-(2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one(90.0 mg, 0.154 mmol) in methanol (3.0 mL). After being stirred at roomtemperature for 2 hours, the reaction mixture was adjusted to pH around8-9 with saturated NaHCO₃, extracted with dichloromethane, dried overNa₂SO₄ and concentrated. The residue was purified with prep-HPLC toafford1-(1-(4-chloro-3-fluorophenyl)-3-hydroxybutyl)-4-(2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one(36 mg, 50% yield) as a solid. ¹H NMR (500 MHz, (CD₃)₂SO) δ 10.92 (s,1H), 8.41 (d, J=5.0 Hz, 1H), 7.95 (m, 1H), 7.58 (m, 1H), 7.46 (m, 1H),7.30 (m, 1H), 7.23 (m, 1H), 7.10 (m, 1H), 7.07 (m, 1H), 6.87 (m, 1H),6.14 (m, 1H), 4.70 (m, 1H), 3.97 (m, 1H), 3.89-3.87 (m, 2H), 3.41-3.33(m, 2H), 2.47 (m, 1H), 2.06 (m, 1H), 1.86-1.84 (m, 2H), 1.56-1.52 (m,2H), 1.12-1.09 (m, 3H); LCMS (ESI) m/z: 473.2 [M+H]⁺.

Example 44

1-(2-hydroxy-1-(1H-indol-2-yl)ethyl)-4-(2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one

Step A: Diisobutylaluminum hydride (159 mL, 159 mmol) was added dropwiseat −60° C. to a solution of methyl 1H-indole-2-carboxylate (10.0 g, 52.9mmol) in THF (100 mL). After being stirred for 1 hour, the reaction wasquenched with saturated NH₄Cl. The resulting mixture was extracted withethyl acetate (2×100 mL) and washed with brine, dried, and concentratedto give (1H-indol-2-yl)methanol (8.0 g, 100% yield) as a solid. LCMS(ESI) m/z: 148.1 [M+H]⁺.

Step B: A mixture of (1H-indol-2-yl)methanol (8.00 g, 54.4 mmol) and2-iodoxybenzoic acid (“IBX”) (40.0 g, 0.163 mol) in ethyl acetate (200mL) was stirred at 80° C. for 16 hours. The solid was filtered off, andthe filtrate was concentrated. The residue was purified by silica gelcolumn chromatography eluting with petroleum ether/ethyl acetate (50:1)to give 1H-indole-2-carbaldehyde (4.0 g, 50% yield) as a solid. LCMS(ESI) m/z: 146.1 [M+H]⁺.

Step C: NaH (2.6 g, 66.2 mmol) at 0° C. was added to a mixture of1H-indole-2-carbaldehyde (4.00 g, 27.6 mmol) and PPh₃CH₃Br (19.7 g, 55.2mmol) in dry THF (100 mL). After being stirred at room temperature for16 hours, the reaction was quenched with water. After partition, theaqueous layer was extracted with ethyl acetate (2×50 mL). The combinedorganic layers were washed with brine, dried, and concentrated. Theresidue was purified by silica gel column chromatography eluting withpetroleum ether/ethyl acetate (50:1) to give 2-vinyl-1H-indole (4.0 g,83% yield) as a solid.

Step D: N,N-Dimethylpyridin-4-amine (100 mg) and triethylamine (7.0 mL,69 mmol) at room temperature were added to a mixture of2-vinyl-1H-indole (4.0 g, 28 mmol) and Boc₂O (7.26 g, 33.6 mmol) in DCM(50 mL). After being stirred for 1 hour, the mixture was concentrated.The residue was purified by silica gel column chromatography elutingwith petroleum ether/ethyl acetate (200:1) to give tert-butyl2-vinyl-1H-indole-1-carboxylate (5.2 g, 76% yield) as an oil.

Step E: 4-Methoxy-4-methylmorpholin-4-ium (1.5 g, 12.8 mmol), water (10mL), and OsO₄ (250 mg, 1 mmol) in water (10 mL) were added to a mixtureof tert-butyl 2-vinyl-1H-indole-1-carboxylate (2.60 g, 10.7 mmol) inacetone (15 mL) and THF (15 mL). After being stirred at room temperaturefor 16 hours, saturated Na₂SO₃ was added, and the resulting mixture wasstirred for 30 minutes. The insoluble material was filtered off. Thefiltrate was extracted with ethyl acetate (2×100 mL), washed with brine,dried, and concentrated to give tert-butyl2-(1,2-dihydroxyethyl)-1H-indole-1-carboxylate (2.0 g, 69% yield) as anoil.

Step F: TBSCl (1.3 g, 8.9 mmol) in dichloromethane (20 mL) was addeddropwise at 0° C. over 10 minutes to a solution of tert-butyl2-(1,2-dihydroxyethyl)-1H-indole-1-carboxylate (2.0 g, 7.2 mmol) andimidazole (1.20 g, 17.4 mmol) in DCM (30 mL). After being stirred atroom temperature for 1 hour, the mixture was washed with water (2×50 mL)and brine, dried, and concentrated. The residue was purified by silicagel column chromatography eluting with petroleum ether/ethyl acetate(50:1) to give an oil, which was further purified by prep-HPLC to affordtert-butyl2-(2-(tert-butyldimethylsilyloxy)-1-hydroxyethyl)-1H-indole-1-carboxylate(500 mg, 18% yield) as an oil. LCMS (ESI) m/z: 318.3 [M-56-17]⁺.

Step G: Triethylamine (68 mg, 0.67 mmol) and methanesulfonyl chloride(71 mg, 0.67 mmol) were added at room temperature to a solution oftert-butyl2-(2-(tert-butyldimethylsilyloxy)-1-hydroxyethyl)-1H-indole-1-carboxylate(240 mg, 0.610 mmol) in DCM (20 mL). After being stirred at roomtemperature overnight, the reaction mixture was diluted withdichloromethane (15 mL). The resulting mixture was further washed withwater (15 mL) and dried over anhydrous Na₂SO₄. After removal of thesolvent, the residue tert-butyl2-(2-(tert-butyldimethylsilyloxy)-1-methylsulfonyloxyethyl)-1H-indole-1-carboxylatewas used directly in the next step.

Step H: Potassium 2-methylpropan-2-olate (114 mg, 1.02 mmol),tetrabutylammonium iodide (57 mg, 0.15 mmol), and a solution oftert-butyl2-(2-(tert-butyldimethylsilyloxy)-1-methylsulfonyloxyethyl)-1H-indole-1-carboxylate(0.61 mmol) in anhydrous THF (15 mL) were added to a suspension of4-(2-(tetrahydro-2H-pyran-4-ylamino)pyrimidin-4-yl)pyridin-2(1H)-one(139 mg, 0.510 mmol) in anhydrous THF (5.0 mL). The resulting mixturewas stirred at 95° C. under microwave irradiation for 2 hours. Thereaction mixture was then treated with water (20 mL) and diluted withDCM. After removal of the insoluble by filtration, the filtrate wasextracted with DCM. The combined organic phase was dried over Na₂SO₄ andconcentrated. The residue was purified with prep-HPLC to afford1-(2-hydroxy-1-(1H-indol-2-yl)ethyl)-4-(2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-oneformate (4.6 mg, 1.1% yield) as a solid. ¹H NMR (500 MHz, (CD₃)₂SO) δ11.20 (s, 1H), 8.46-8.40 (m, 2H), 7.64 (d, J=7.0 Hz, 1H), 7.50 (d, J=8.5Hz, 1H), 7.35-7.31 (m, 2H), 7.14-7.12 (m, 2H), 7.06 (m, 1H), 6.97 (m,1H), 6.81 (d, J=7.0 Hz, 1H), 6.54 (s, 1H), 6.24 (m, 1H), 5.30 (m, 1H),4.13-4.07 (m, 2H), 3.97 (m, 1H), 3.88-3.86 (m, 2H), 3.41-3.36 (m, 2H),1.85-1.83 (m, 2H), 1.56-1.49 (m, 2H); LCMS (ESI) m/z: 432.2 [M+H]⁺.

Example 45

1-((R)-(4-chloro-3-fluorophenyl)((R)-pyrrolidin-3-yl)methyl)-4-(2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one

Step A: (R)-1-(tert-Butoxycarbonyl)pyrrolidine-3-carboxylic acid (922.3mg, 4.285 mmol) was dissolved in dichloromethane (42.8 mL, 0.1M) at roomtemperature under nitrogen and was treated withN,O-dimethylhydroxylamine hydrochloride (501.6 mg, 5.142 mmol),O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethylurea (1955 mg, 5.142mmol), and N,N-diisopropylethylamine (1493 μL, 8.570 mmol). The mixturewas stirred at room temperature for 2 hours. The reaction was thendiluted to 100 mL with dichloromethane and washed with water (100 mL).The water layer was back extracted with 4/1 dichloromethane/isopropanol(2×50 mL). The combined organics were washed with water (100 mL), wereisolated, dried over sodium sulfate, filtered and concentrated to anoil. The crude product was loaded onto an SP1 samplet and purified bysilica gel chromatography using a gradient from 10% to 70% acetone inhexanes. Product containing fractions (ninhydrin visualization) werepooled and concentrated to afford (R)-tert-butyl3-(methoxy(methyl)carbamoyl)pyrrolidine-1-carboxylate as an oil (1.1gram, 100% yield).

Step B: (R)-tert-Butyl3-(methoxy(methyl)carbamoyl)pyrrolidine-1-carboxylate (1.107 g, 4.285mmol) was dissolved in THF (21.4 mL, 0.2M), cooled to 0° C., anddegassed with N₂. 4-Chloro-3-fluorophenylmagnesium bromide (0.5M in THF;17.14 mL, 8.571 mmol) was added drop wise by syringe, and the reactionwas then stirred at 0° C. for 1.5 hours. Water (10 mL) was then added toquench the reaction. The mixture was concentrated by rotovap to removethe bulk of the THF. The remaining mixture was diluted to 50 mL withwater and extracted with 4/1 dichloromethane/isopropyl alcohol (2×50mL). The combined organics were washed with water (100 mL), wereisolated, dried over sodium sulfate, filtered and concentrated. Thecrude product was loaded onto an SP1 samplet and purified by silica gelchromatography using a gradient from 2% to 50% ethyl acetate in hexanes.Product containing fractions were pooled and concentrated to afford(R)-tert-butyl 3-(4-chloro-3-fluorobenzoyl)pyrrolidine-1-carboxylate asan oil (920 mg, 65% yield).

Step C: (R)-tert-Butyl3-(4-chloro-3-fluorobenzoyl)pyrrolidine-1-carboxylate (920 mg, 2.806mmol) was dissolved in THF (14.0 mL, 0.2M), degassed with N₂, and cooledto −78° C. Lithium tri-sec-butylborohydride (1M in THF; 4210 μL, 4.210mmol) was added slowly drop wise by syringe. The reaction was thenstirred at −78° C. for 30 minutes. Water (5 mL) was then added to quenchthe reaction. The mixture was concentrated by rotovap to remove the bulkof the THF. The remaining mixture was diluted to 50 mL with water andextracted with 4/1 dichloromethane/isopropyl alcohol (2×50 mL). Thecombined organics were washed with water (100 mL), were isolated, driedover sodium sulfate, filtered and concentrated. The crude product wasloaded onto an SP1 samplet and purified by silica gel chromatographyusing a gradient from 1% to 55% ethyl acetate in hexanes. Productcontaining fractions were pooled and concentrated to afford(3R)-tert-butyl3-((4-chloro-3-fluorophenyl)(hydroxy)methyl)pyrrolidine-1-carboxylate asan oil and as a 1:1 mixture of diastereomers (640 mg, 69% yield).

Step D: (3R)-tert-Butyl3-((4-chloro-3-fluorophenyl)(hydroxy)methyl)pyrrolidine-1-carboxylate(640 mg, 1.943 mmol) was dissolved in DCM (4.9 mL, 0.2M) under nitrogen,treated with triphenylphosphine (637.0 mg, 2.429 mmol) and cooled to 0°C. Diisopropyl azodicarboxylate (478.2 μL, 2.429 mmol) was added bysyringe. After 5 minutes, the mixture was warmed to room temperature andstirred for 10 minutes prior to being treated with4-(2-(methylthio)pyrimidin-4-yl)pyridin-2(1H)-one (213 mg, 0.9714 mmol).The mixture was then stirred at room temperature for 16 hours. Afterconcentration by rotovap and high vacuum, the mixture was loaded onto aC18 reverse phase column and eluted with a gradient of 5% acetonitrileto 100% acetonitrile in water. The mixture of diastereomers isolatedwere then loaded onto an SP1 samplet and purified by silica gelchromatography using a 20% to 80% gradient of MTBE in dichloromethane.Fractions containing each diastereomer were isolated and concentrated toafford (R)-tert-butyl3-((R)-(4-chloro-3-fluorophenyl)(4-(2-(methylthio)pyrimidin-4-yl)-2-oxopyridin-1(2H)-yl)methyl)pyrrolidine-1-carboxylatefrom the higher rf spot and (R)-tert-butyl3-((S)-(4-chloro-3-fluorophenyl)(4-(2-(methylthio)pyrimidin-4-yl)-2-oxopyridin-1(2H)-yl)methyl)pyrrolidine-1-carboxylateas the lower rf spot, both as oils (54 mg, 10% yield and 48 mg, 9% yieldrespectively).

Step E: (R)-tert-Butyl3-((R)-(4-chloro-3-fluorophenyl)(4-(2-(methylthio)pyrimidin-4-yl)-2-oxopyridin-1(2H)-yl)methyl)pyrrolidine-1-carboxylate(54.5 mg, 0.103 mmol) was dissolved in DCM (1.0 mL, 0.1 M) at roomtemperature under nitrogen and treated with 3-chloroperoxybenzoic acid(75.9 mg, 0.308 mmol). After stirring for 1 hour, the mixture wasdiluted with EtOAc (15 mL) and washed with 10% sodium thiosulfate (15mL) and brine (15 mL). The isolated organics were then dried over sodiumsulfate, filtered and concentrated. The crude product was loaded onto anSP1 samplet and purified by silica gel chromatography using a 2% to 50%gradient of acetone in dichloromethane to afford (R)-tert-butyl3-((R)-(4-chloro-3-fluorophenyl)(4-(2-(methylsulfonyl)pyrimidin-4-yl)-2-oxopyridin-1(2H)-yl)methyl)pyrrolidine-1-carboxylateas a solid (45 mg, 78% yield).

Step F: (R)-tert-Butyl3-((R)-(4-chloro-3-fluorophenyl)(4-(2-(methylsulfonyl)pyrimidin-4-yl)-2-oxopyridin-1(2H)-yl)methyl)pyrrolidine-1-carboxylate(45.1 mg, 0.0801 mmol) was dissolved in DMA (1.0 mL, 0.1M) at roomtemperature under nitrogen and treated with tetrahydro-2H-pyran-4-amine(40.5 mg, 0.401 mmol). The solution was heated to 120° C. for 1 hour inthe microwave. The reaction was then diluted with EtOAc (15 mL) andwashed with water (3×15 mL) and brine (15 mL). The organics wereisolated, dried over sodium sulfate, filtered and concentrated. Thecrude product was loaded onto an SP1 samplet and purified by silica gelchromatography using a 10% to 80% gradient of acetone in hexanes.Product containing fractions were pooled, concentrated and thenredissolved in dichloromethane (2 mL) and treated with 1:1 TFA/DCM (1.0mL) and stirred at room temperature for 1 hour. The reaction was dilutedto 15 mL with additional DCM and washed with NaHCO₃ (2×15 mL). Theorganics were isolated, dried over sodium sulfate, filtered andconcentrated to afford1-((R)-(4-chloro-3-fluorophenyl)((R)-pyrrolidin-3-yl)methyl)-4-(2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-oneas an oil. ¹H NMR (400 MHz, ((CD₃)₂SO) δ 8.40 (d, 1H), 8.04 (d, 1H),7.62 (m, 2H), 7.37 (d, 1H), 7.34 (br s, 1H), 7.13 (d, 1H), 7.08 (s, 1H),6.86 (d, 1H), 5.84 (br s, 1H), 3.97 (m, 1H), 3.87 (m, 2H), 3.38 (m, 2H),2.86 (m, 1H), 2.79 (m, 2H), 2.34 (m, 1H), 1.84 (br d, 2H), 1.74 (m, 1H),1.52 (m, 3H), 1.27 (m, 2H); LCMS (ESI) m/z 484.1 [M+H+].

Example 46

2-(3-fluoro-4-methoxyphenyl)-2-(2-oxo-4-(2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)pyridin-1(2H)-yl)acetic acid

Step A: A 500 mL 24/40 round bottomed flask equipped with a stirring barwas charged with (3-fluoro-4-methoxyphenyl)acetic acid methyl ester(4.17 g) and dissolved in anhydrous carbon tetrachloride (200 mL).N-Bromosuccinimide (“NBS”) (4.89 g) was added, followed by benzoylperoxide (“BPO”) (550 mg). The flask was equipped with a water cooledcondenser and placed in a pre-heated 100° C. oil bath. After refluxingfor 17.5 hours, the flask was removed from the oil bath, cooled to roomtemperature and filtered. The filtrate was analyzed by LCMS and TLC.Since the starting material and both products did not ionize well, TLC(40% ethyl acetate/heptane) was used to determine conversion of startingmaterial to product. TLC indicated the starting material had beencompletely consumed. The filtrate was concentrated to a residue,dissolved in a minimal amount of DCM and adsorbed onto a silicapre-column. After ISCO purification (80 g column, 0-100% ethylacetate/heptane over 25 column volumes) fractions for the major uvproduct (30-40% ethyl acetate) were combined and concentrated to yieldmethyl 2-bromo-2-(3-fluoro-4-methoxyphenyl)acetate (4.73 g). The NMR inCDCl₃ was consistent with methyl2-bromo-2-(3-fluoro-4-methoxyphenyl)acetate and matched that reported inWO 2007/024945. The fractions for a second minor uv active product(50-60% ethyl acetate) were combined and concentrated. NMR indicated thedi-brominated compound methyl2,2-dibromo-2-(3-fluoro-4-methoxyphenyl)acetate (0.539 g, 6.7%).

Step B: A 25 mL oven dried round bottom flask equipped with a stirringbar that had been cooled under nitrogen was charged with4-[2-(tetrahydropyran-4-ylamino)pyrimidin-4-yl]-1H-pyridin-2-one (553mg, 2.031 mmol). The solid was dissolved in anhydrous THF (10 mL,0.203M), cooled to 0° C. and treated with 1M lithiumhexamethyldisilazide in tetrahydrofuran (3.6 mL, 1.8 equivalents, 3.66mmol). The ice bath was removed, and the reaction mixture warmed to roomtemperature. With vigorous stirring at room temperature, a THF solution(2.0 mL) of methyl 2-bromo-2-(3-fluoro-4-methoxy-phenyl)acetate (563 mg,1.0 equivalent, 2.031 mmol) was added drop wise over 2 minutes. Thereaction mixture was stirred at room temperature for 16 hours andconcentrated to a residue. LCMS indicated the major new product was theacid resulting from hydrolysis of the methyl ester. The residue wasdissolved in methanol (15 mL) and purified by preparative RP HPLC (5injections×3 mL/per inject, 0-80% CH₃CN/H₂O with 0.1% FA over 14minutes). Fractions containing the desired M+H+ and >90% purity from allruns were combined and lyophilized to yield2-(3-fluoro-4-methoxyphenyl)-2-(2-oxo-4-(2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)pyridin-1(2H)-yl)aceticacid (89 mg, 10% yield, 94.2% purity uv, 254 nm). ¹H NMR (400 MHz,(CD₃)₂SO) δ 8.41 (d, J=5.1 Hz, 1H), 7.44 (d, J=7.3 Hz, 1H), 7.34 (m,2H), 7.25 (m, 2H), 7.12 (br s, 2H), 6.81 (d, J=7.0 Hz, 1H), 6.32 (s,1H), 4.13-3.91 (m, 1H), 3.90-3.83 (m, 2H), 3.89 (s, 3H), 3.38 (m and H₂O2H), 1.85 (m, 2H), 1.53 (dq, J=12.0, 4.4 Hz, 2H); LC-MS: m/z=+455.17(M+H)⁺.

Example 47

1-(1-(4-chloro-3-fluorophenyl)vinyl)-4-(2-((1,3-dimethyl-1H-pyrazol-5-ylamino)pyrimidin-4-yl)pyridin-2(1H)-one

A 2-5 mL microwave vial equipped with a stirring bar was charged with1-[(1S)-2-[tert-butyl(dimethyl)silyl]oxy-1-(4-chloro-3-fluoro-phenyl)ethyl]-4-(2-methylsulfonylpyrimidin-4-yl)pyridin-2-one(100 mg, 0.1858 mmol, 1.0 equivalent) and 2,5-dimethylpyrazol-3-amine(41.31 mg, 0.3717 mmol, 2.0 equivalents). The solids were dissolved indimethyl formamide (3.0 mL), and sodium hydride (14.08 mg, 0.5575 mmol,3.0 equivalents, 60% dispersion in mineral oil) was added at roomtemperature. The microwave vial was capped, placed in a microwavereactor and heated at 160° C. for 10 minutes. The vial was cooled toroom temperature, uncapped and analyzed by LCMS. The major uv activeproduct exhibited an a M+H+ consistent with1-(1-(4-chloro-3-fluorophenyl)vinyl)-4-(2-((1,3-dimethyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one.The reaction mixture was partitioned between water/EtOAc. The ethylacetate layer was washed with brine, dried (Na₂SO₄), filtered andconcentrated to a crude semi-solid residue. The residue was purified byRP HPLC to yield1-(1-(4-chloro-3-fluorophenyl)vinyl)-4-(2-((1,3-dimethyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one(11.7 mg, 14% yield, 99.5% purity, uv 254 nm). ¹H NMR (400 MHz,(CD₃)₂SO) δ 9.53 (s, 1H), 8.61 (d, J=5.1 Hz, 1H), 7.79 (d, J=7.2 Hz 1H),7.58 (t, J=8.2 Hz 1H), 7.53-7.44 (m, 2H), 7.15 (d, J=1.6 Hz, 1H), 7.07(dd, J=8.5, 2.0 Hz, 1H), 6.96 (dd, J=7.1, 1.8 Hz 1H), 6.22 (d, J=1.5 Hz1H), 6.05 (s, 1H), 5.63 (d, J=1.4 Hz, 1H), 3.61 (s, 3H), 2.12 (s, 3H);LCMS: m/z=+437.12 (M+H)+.

Example 48

1-((S)-1-(4-chloro-3-fluorophenyl)-2-hydroxyethyl)-4-(2-(3-oxo-2-oxabicyclo[2.2.1]heptan-5-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one

Step A: A mixture of benzyl 2-oxa-bicyclo[2.2.1]heptan-5-ylcarbamate(0.05 g, 2.0 mmol) and Pd/C (10%, 50 mg) in methanol (20 mL) was stirredunder hydrogen atmosphere (1 atm) at room temperature for 16 hours.After completion of the reaction, the mixture was filtered throughCelite®. The filtrate was concentrated under reduced pressure to afford5-amino-2-oxa-bicyclo[2.2.1]heptan-3-one (360 mg, over 100%), which wasused in the next step without further purification. LCMS (ESI) m/z:128.1 [M+H]⁺.

Step B: A microwave vial was charged with1-(2-(tert-butyldimethylsilyloxy)-1-(4-chloro-3-fluorophenyl)ethyl)-4-(2-(methylsulfonyl)pyrimidin-4-yl)pyridin-2(1H)-one(150 mg, 0.280 mmol), 5-amino-2-oxa-bicyclo[2.2.1]heptan-3-one (89 mg,0.70 mmol), a drop of concentrated HCl, and s-butanol (2.0 mL). Themixture was stirred at 130° C. under microwave irradiation for 3 hours.After completion of the reaction, the mixture was concentrated to give1-((S)-2-(tert-butyldimethylsilyloxy)-1-(4-chloro-3-fluorophenyl)ethyl)-4-(2-(3-oxo-2-oxa-bicyclo[2.2.1]heptan-5-ylamino)pyrimidin-4-yl)pyridin-2(1H)-one(164 mg, 100% yield), which was used in the next step without furtherpurification. LCMS (ESI) m/z: 285.2 [M+H]⁺.

Step C: TBAF (80 mg, 0.31 mmol) was added to a solution of1-((S)-2-(tert-butyldimethylsilyloxy)-1-(4-chloro-3-fluorophenyl)ethyl)-4-(2-(3-oxo-2-oxa-bicyclo[2.2.1]heptan-5-ylamino)pyrimidin-4-yl)pyridin-2(1H)-one(164 mg, 0.280 mmol) in THF (10 mL). After being stirred at roomtemperature for 16 hours, the reaction mixture was diluted with ethylacetate (100 mL), washed with water (5×30 mL). The organic layer wasdried over Na₂SO₄ and concentrated. The residue was purified byprep-HPLC to afford1-((S)-1-(4-chloro-3-fluorophenyl)-2-hydroxyethyl)-4-(2-(3-oxo-2-oxabicyclo[2.2.1]heptan-5-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one(6 mg, 5% yield). ¹H NMR (500 MHz, CDCl₃) δ 8.45 (d, J=3 Hz, 1H), 7.43(t, J=13.5 Hz, 2H), 7.20 (d, J=10 Hz, 1H), 5.27 (d, J=5.5, 1H), 5.03 (s,1H), 4.16 (s, 1H), 4.33 (d, J=5 Hz, 2H), 3.21 (s, 1H), 2.62 (s, 3H),2.32 (t, J=13.5 Hz, 1H), 2.02 (d, J=10.5 Hz, 1H), 1.69 (d, J=4.5 Hz,1H); LCMS (ESI) m/z: 471.1 [M+H]⁺.

Example 49

1-(2-(4-chloro-3-fluorophenyl)-2,3-dihydroxypropyl)-4-(2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one

Step A: n-BuLi (2.5N, 8.0 mL) was added at −78° C. to a mixture ofmethyltriphenylphosphonium bromide (5.6 g, 0.15 mol) in THF (50 mL).After being stirred for 0.5 hours,2-(tert-butyldimethylsilyloxy)-1-(4-chloro-3-fluorophenyl)ethanone (3.9g, 0.013 mol) was added to the reaction mixture. The mixture was thenstirred for 2 hours at 25° C. After quenching with saturated NH₄Cl (100mL), the reaction mixture was extracted with ethyl acetate (3×50 mL).The combined organic layers were dried and concentrated. The residue waspurified by silica gel column chromatography eluting with petroleumether to give tert-butyl(2-(4-chloro-3-fluorophenyl)allyloxy)dimethylsilane (1.6 g, 40% yield).

Step B: mCPBA (372 mg, 2.20 mmol) was added to a solution of tert-butyl(2-(4-chloro-3-fluorophenyl)allyloxy)dimethylsilane (450 mg, 1.50 mmol)in CH₂Cl₂ (10 mL). After being stirred at room temperature overnight,the reaction was quenched with Na₂S₂O₃ (10%, 2×10 mL). The organic layerwas washed with saturated Na₂CO₃ (3×10 mL), dried over Na₂SO₄, andconcentrated to give tert-butyl(2-(4-chloro-3-fluorophenyl)oxiran-2-yloxy)dimethylsilane (490 mg, over100% yield).

Step C:4-(2-(Tetrahydro-2H-pyran-4-ylamino)pyrimidin-4-yl)pyridin-2(1H)-one(136 mg, 0.500 mmol) and K₂CO₃ (248 mg, 1.80 mmol) were added to asolution of tert-butyl(2-(4-chloro-3-fluorophenyl)oxiran-2-yloxy)dimethylsilane (200 mg, 0.600mmol) in DMF (5.0 mL). After being heated at 80° C. overnight, themixture was diluted with H₂O (50 mL) and extracted with EtOAc (3×100mL). The organic phases were washed with brine (3×30 mL), dried, andconcentrated. The residue was dissolved in CH₂Cl₂, followed by additionof TFA (5.0 mL). The mixture was stirred at room temperature overnight.The solvent was removed under vacuum, and the residue was purified byprep-HPLC to give1-(2-(4-chloro-3-fluorophenyl)-2,3-dihydroxypropyl)-4-(2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)pyridine-2(1H)-one(70 mg, 30% yield). ¹H NMR (500 MHz, CD₃OD) δ 8.39 (m, 1H), 7.67-7.66(m, 1H), 7.51-7.49 (m, 1H), 7.45-7.38 (m, 1H), 7.22 (s, 2H), 7.08-7.07(m, 1H), 6.97-6.95 (m, 1H), 4.69-4.66 (m, 1H), 4.31-4.28 (m, 1H), 4.10(s, 1H), 4.01-3.99 (m, 2H), 3.72-3.66 (m, 2H), 3.60-3.56 (m, 2H),2.03-2.00 (m, 2H), 1.67-1.59 (m, 2H); LCMS (ESI) m/z: 475.1 [M+H]⁺.

The following compounds in Table 2 were prepared according to the aboveprocedures using appropriate starting materials and intermediates.

TABLE 2 Ex. # Structure Name MS 50

1-((S)-(3-fluoro-4- methoxyphenyl)((R)-pyrrolidin-2-yl)methyl)-4-(2-((tetrahydro-2H- pyran-4-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one m/z (APCI- pos) M +1 = 480.2, 482.2 51

1-(1-phenylethyl)-4-(2-((tetrahydro- 2H-pyran-4-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one m/z (APCI- pos) M + 1 = 377.2 52

4-(2-(((S)-1-hydroxypropan-2- yl)amino)pyrimidin-4-yl)-1-(1-phenylethyl)pyridin-2(1H)-one m/z (APCI- pos) M + 1 = 351.2 53

1-(2-hydroxy-1-phenylethyl)-4-(2- ((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)pyridin- 2(1H)-one m/z (APCI- pos) M + 1 = 393.254

1-(2-hydroxy-1-phenylethyl)-4-(2- (((S)-1-hydroxypropan-2-yl)amino)pyrimidin-4-yl)pyridin- 2(1H)-one m/z (APCI- pos) M + 1 = 367.155

1-(1-(4-chlorophenyl)-2- hydroxyethyl)-4-(2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4- yl)pyridin-2(1H)-one m/z (APCI- pos) M + 1= 427.1, 429.1 56

1-(1-(4-chlorophenyl)-2- hydroxyethyl)-4-(2-(((S)-1- hydroxypropan-2-yl)amino)pyrimidin-4-yl)pyridin- 2(1H)-one m/z (APCI- pos) M + 1 =401.1, 403.1 57

(S)-1-(1-(3-chlorophenyl)-2- hydroxyethyl)-4-(2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4- yl)pyridin-2(1H)-one m/z (APCI- pos) M + 1= 427.1, 429.1 58

1-(1-(3-chlorophenyl)-2- hydroxyethyl)-4-(2-(((S)-1- hydroxypropan-2-yl)amino)pyrimidin-4-yl)pyridin- 2(1H)-one m/z (APCI- pos) M + 1 =401.1, 403.1 59

1-(1-(3-chlorophenyl)-2- hydroxyethyl)-4-(2-(isopropylamino)pyrimidin-4- yl)pyridin-2(1H)-one m/z (APCI- pos) M + 1= 385.1, 387.1 60

1-(1-(3-chloro-4-fluorophenyl)-2- hydroxyethyl)-4-(2-(((S-1-hydroxypropan-2- yl)amino)pyrimidin-4-yl)pyridin- 2(1H)-one m/z (APCI-pos) M + 1 = 419.1, 421.1 61

1-(1-(3-chloro-4-fluorophenyl)-2- hydroxyethyl)-4-(2-(((1S,3S)-3-hydroxycyclopentyl)amino)pyrimidin- 4-yl)pyridin-2(1H)-one m/z (APCI-pos) M + 1 = 445.1, 447.1 62

1-(1-(3-chloro-4-fluorophenyl)-2- hydroxyethyl)-4-(2-(((S)-1-hydroxybutan-2-yl)amino)pyrimidin- 4-yl)pyridin-2(1H)-one m/z (APCI-pos) M + 1 = 433.1, 435.1 63

1-(1-(4-chloro-3-fluorophenyl)-2- hydroxyethyl)-4-(2-((tetrahydro-2H-dioxo-thiopyran-4- yl)amino)pyrimidin-4-yl)pyridin- 2(1H)-one m/z (APCI-neg) M − 1 = 491.1, 493.0 64

1-(1-(4-chloro-3-fluorophenyl)-2- hydroxyethyl)-4-(2-(((R)-1-cyclopropylethyl)amino)pyrimidin yl)pyridin-2(1H)-one m/z (APCI- pos)M + 1 = 429.1, 431.1 65

1-((S)-1-(4-chloro-3-fluorophenyl)-2-hydroxyethyl)-4-(2-(((R)-1-hydroxy- 3-methoxypropan-2-yl)amino)pyrimidin-4-yl)pyridin- 2(1H)-one m/z (APCI- pos) M + 1 =449.1, 451.1 66

(S)-1-(1-(4-chloro-3-fluorophenyl)-2- hydroxyethyl)-5-methyl-4-(2-((tetrahydro-2H-pyran-4- yl)amino)pyrimidin-4-yl)pyridin- 2(1H)-one m/z(APCI- pos) M + 1 = 459.1, 461.1 67

(S)-1-(1-(4-chloro-3-fluorophenyl)-2- hydroxyethyl)-4-(2-((1-methyl-1H-pyrazol-3-yl)amino)pyrimidin-4- yl)pyridin-2(1H)-one m/z (APCI- pos) M +1 = 441.1, 443.1 68

(S)-1-(1-(4-chloro-3-fluorophenyl)-2- hydroxyethyl)-6-methyl-4-(2-((tetrahydro-2H-pyran-4- yl)amino)pyrimidin-4-yl)pyridin- 2(1H)-one m/z(APCI- pos) M + 1 = 459.1, 461.1 69

(S)-1-(1-(4-chloro-3-fluorophenyl)-2- hydroxyethyl)-4-(2-((1,3-difluoropropan-2-yl)amino)pyrimidin- 4-yl)pyridin-2(1H)-one m/z (APCI-pos) M + 1 = 439.1, 441.1 70

1-((S)-1-(4-chloro-3-fluorophenyl)-2- hydroxyethyl)-4-(2-((1,1-dioxidotetrahydrothiophen-3- yl)amino)pyrimidin-4-yl)pyridin- 2(1H)-onem/z (APCI- neg) M − 1 = 479.0, 481.0 71

1-(1-(3-chloro-4-fluorophenyl)-2- hydroxyethyl)-4-(2-(((S)-1-cyclopropyl-2-hydroxyethyl) amino)pyrimidin-4-yl)pyridin-2(1H)- one m/z(APCI- neg) M − 1 = 445.1, 447.1 72

1-((R)-1-(3-chlorophenyl)propyl)-4-(2-((1,1-dioxidotetrahydrothiophen-3- yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one m/z (APCI- neg) M − 1 = 459.1, 460.0 73

1-((R)-1-(3-chlorophenyl)propyl)-4- (2-(((1S,3S)-3-hydroxycyclopentyl)amino) pyrimidin-4-yl)pyridin-2(1H)-one m/z (APCI-neg) M − 1 = 425.1, 427.1 74

(S)-1-(1-(4-chloro-3-fluorophenyl)-2- hydroxyethyl)-4-(2-((oxetan-3-ylmethyl)amino)pyrimidin-4- yl)pyridin-2(1H)-one m/z (APCI- pos) M + 1 =431.1 75

(S)-4-(5-f1uoro-2-((tetrahydro-2H- pyran-4-yl)amino)pyrimidin-4-yl)-1-(1-(3-fluorophenyl)-2- hydroxyethyl)pyridin-2(1H)-one m/z (APCI- pos)M + 1 = 429.1 76

(S)-4-(5-chloro-2-((tetrahydro-2H- pyran-4-yl)amino)pyrimidin-4-yl)-1-(1-(4-chloro-3-fluorophenyl)-2- hydroxyethyl)pyridin-2(1H)-one m/z(APCI- pos) M + 1 = 479.0, 481 (73%) 77

(R)-1-(1-3-chlorophenyl)propyl)-4- (2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)pyridin- 2(1H)-one m/z (APCI- pos) M + 1 =425.1, 426.1 78

(S)-1-(1-(4-chloro-3-fluorophenyl)-2- hydroxyethyl)-4-(2-((oxetan-3-yl)amino)pyrimidin-4-yl)pyridin- 2(1H)-one m/z (APCI- pos) M + 1 =417.1, 419.1 79

(S)-1-(1-(3,4-difluorophenyl)-2- hydroxyethyl)-4-(2-((tetrahydro-pyran-4-yl)amino)pyrimidin-4- yl)pyridin-2(1H)-one m/z (APCI- pos) M + 1= 429.1 80

(S)-1-(1-(3-chloro-2-fluorophenyl)-2-hydroxyethyl)-4-(2-((tetrahydro-2H- pyran-4-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one m/z (APCI- pos) M + 1 = 445.0, 447.1 81

(S)-1-(1-(3-chloro-5-fluorophenyl)-2-hydroxyethyl)-4-(2-((tetrahydro-2H- pyran-4-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one m/z (APCI- pos) M + 1 = 445.1, 447.1 82

1-(1-(3-fluorophenyl)-2- hydroxyethyl)-4-(2-(((S)-1- hydroxypropan-2-yl)amino)pyrimidin-4-yl)pyridin- 2(1H)-one m/z (APCI- pos) M + 1 = 385.183

1-(1-(3,5-difluorophenyl)-2- hydroxyethyl)-4-(2-(((S)-1-hydroxypropan-2- yl)amino)pyrimidin-4-yl)pyridin- 2(1H)-one m/z (APCI-pos) M + 1 = 403.1 84

1-(1-(3,5-dichlorophenyl)-2- hydroxyethyl)-4-(2-(((S)-1-hydroxypropan-2- yl)amino)pyrimidin-4-yl)pyridin- 2(1H)-one (APCI- pos)M + 1 = 435.1, 437.0 85

1-(1-(3-chloro-5-fluorophenyl)-2- hydroxyethyl)-4-(2-(((S)-1-hydroxypropan-2- yl)amino)pyrimidin-4-yl)pyridin- 2(1H)-one m/z (APCI-pos) M + 1 = 419.1, 421.1 86

1-(2-hydroxy-1-(3- (trifluoromethyl)phenyl)ethyl)-4-(2-((tetrahydro-2H-pyran-4- yl)amino)pyrimidin-4-yl)pyridin- 2(1H)-one m/z(APCI- pos) M + 1 = 461.1 87

1-(2-hydroxy-1-m-tolylethyl)-4-(2- ((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)pyridin- 2(1H)-one m/z (APCI- pos) M + 1 = 407.188

3-(2-hydroxy-1-(2-oxo-4-(2- ((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)pyridin- 1(2H)-yl)ethyl)benzonitrile m/z (APCI-pos) M + 1 = 418.1 89

1-(2-hydroxy-1-(3- methoxyphenyl)ethyl)-4-(2- ((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)pyridin- 2(1H)-one m/z (APCI- pos) M + 1 = 423.190

1-((3-chlorophenyl)((S)-pyrrolidin-3- yl)methyl)-4-(2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4- yl)pyridin-2(1H)-one m/z (APCI- pos) M + 1= 466.1, 467.1 91

1-((S)-1-(4-chloro-3-fluorophenyl)-2- hydroxyethyl)-4-(2-(((R)-tetrahydrofuran-3- yl)amino)pyrimidin-4-yl)pyridin- 2(1H)-one m/z (APCI-pos) M + 1 = 431.1, 433.1 92

1-((S)-1-(4-chloro-3-fluorophenyl)-2- hydroxyethyl)-4-(2-(((S)-tetrahydrofuran-3- yl)amino)pyrimidin-4-yl)pyridin- 2(1H)-one m/z (APCI-pos) M + 1 = 431.1, 433.1 93

(S)-1-(1-(3,4-difluorophenyl)-2- hydroxyethyl)-4-(2-((oxetan-3-yl)amino)pyrimidin-4-yl)pyridin- 2(1H)-one m/z (APCI- pos) M + 1 = 401.194

(S)-1-(1-(4-chloro-3-fluorophenyl)-2- hydroxyethyl)-4-(2-((3,3-difluorocyclobutyl)amino)pyrimidin- 4-yl)pyridin-2(1H)-one m/z (APCI-pos) M + 1 = 451.1, 453.1 95

(S)-1-(1-(2-chlorophenyl)-2- hydroxyethyl)-4-(2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4- yl)pyridin-2(1H)-one m/z (APCI- pos) M + 1= 427.1, 429.1 96

1-((R-(4-chloro-3-fluorophenyl)((S)- pyrrolidin-3-yl)methyl)-4-(2-((tetrahydro-2H-pyran-4- yl)amino)pyrimidin-4-yl)pyridin- 2(1H)-one m/z(APCI- pos) M + 1 = 484.1, 485.1 97

1-(1-(3-chlorophenyl)propyl)-4-(2- (((S)-1-hydroxypropan-2-yl)amino)pyrimidin-4-yl)pyridin- 2(1H)-one m/z (APCI- pos) M + 1 =399.1, 401.1 98

(S)-1-(1-(4-(difluoromethoxy)phenyl)- 2-hydroxyethyl)-4-(2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4- yl)pyridin-2(1H)-one m/z (APCI- pos)M + 1 = 459.1 99

(S)-1-(1-(2,3-dichlorophenyl)-2- hydroxyethyl)-4-(2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4- yl)pyridin-2(1H)-one m/z (APCI- pos) M + 1= 461.1, 463.1 100

(S)-1-(1-(2,4-dichlorophenyl)-2- hydroxyethyl)-4-(2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4- yl)pyridin-2(1H)-one m/z (APCI- pos) M + 1= 461.1, 463.0 101

(S)-1-(1-phenylethyl)-4-(2- ((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)pyridin- 2(1H)-one m/z (APCI- pos) M +1 = 377.2102

1-((4-chloro-3-fluorophenyl)((S)- pyrrolidin-2-yl)methyl)-4-(2-((tetrahydro-2H-pyran-4- yl)amino)pyrimidin-4-yl)pyridin- 2(1H)-one m/z(APCI- pos) M + 1 = 484.1, 485.1 103

(S)-1-(1-(3,5-difluorophenyl)-2- hydroxyethyl)-4-(2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4- yl)pyridin-2(1H)-one m/z (APCI- pos) M + 1= 429.1 104

(S)-1-(1-(5-chloropyridin-3-yl)-2- hydroxyethyl)-4-(2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4- yl)pyridin-2(1H)-one m/z (APCI- pos) M + 1= 428.1, 430.1 105

(S)-(1-(1,3-dimethyl-1H-pyrazol-5-yl)-2-hydroxyethyl)-4-(2-((tetrahydro- 2H-pyran-4-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one m/z (APCI- pos) M + 1 = 411.2 106

(R)-1-(1-(4-chloro-3-fluorophenyl)-3-hydroxypropyl)-4-(6-((tetrahydro-2H- pyran-4-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one m/z (APCI- pos) M + 1 = 459.0 107

(S)-1-(1-(4-chloro-3-fluorophenyl)-3-hydroxypropyl)-4-(2-((tetrahydro-2H- pyran-4-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one m/z (APCI- pos) M + 1 = 459.0 108

(R)-1-(1-(4-chloro-3-fluorophenyl)-3-hydroxypropyl)-4-(2-((tetrahydro-2H- pyran-4-yl)amino)pyridin-4-yl)pyridin-2(1H)-one m/z (APCI- pos) M + 1 = 458.0 109

(S)-1-(1-(4-chloro-3-fluorophenyl)-2-hydroxyethyl)-4-(6-((tetrahydro-2H- pyran-4-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one m/z (APCI- pos) M + 1 = 445.0 110

(S)-1-(1-(4-chloro-3-fluorophenyl)-2-hydroxyethyl)-4-(2-((tetrahydro-2H- pyran-4-yl)amino)pyridin-4-yl)pyridin-2(1H)-one m/z (APCI- pos) M + 1 = 444.0 111

(R)-1-(1-(4-chloro-3-fluorophenyl)-3- hydroxypropyl)-4-(2-((6-methoxypyridin-3- yl)amino)pyrimidin-4-yl)pyridin- 2(1H)-one m/z (APCI-pos) M + 1 = 482.1 112

(R)-1-(1-(4-chloro-3-fluorophenyl)-3- hydroxypropyl)-4-(2-)(6-oxo-1,6-dihydropyridin-3-yl)amino)pyrimidin- 4-yl)pyridin-2(1H)-one m/z (APCI-pos) M + 1 = 468.1 113

1-(1-(4-chloro-3-fluorophenyl)-2- hydroxyethyl)-4-(2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4- yl)pyridin-2(1H)-one 445.1 114

1-(1-(3-chlorophenyl)-2- hydroxyethyl)-4-(2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4- yl)pyridin-2(1H)-one 427.1 115

1-(1-(3-chloro-4-fluorophenyl)-2- hydroxyethyl)-4-(2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4- yl)pyridin-2(1H)-one 445.1 116

(R)-1-(1-(4-chloro-3-fluorophenyl)-2-hydroxyethyl)-4-(2-((tetrahydro-2H- pyran-4-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one 444.1 117

1-(1-(3-fluorophenyl)-2- hydroxyethyl)-4-(2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4- yl)pyridin-2(1H)-one 411.1 118

1-(1-(3,5-difluorophenyl)-2- hydroxyethyl)-4-(2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4- yl)pyridin-2(1H)-one 429.1 119

1-(1-(3,5-dichlorophenyl)-2- hydroxyethyl)-4-(2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4- yl)pyridin-2(1H)-one 461.1 120

1-(1-(3-chloro-5-fluorophenyl)-2- hydroxyethyl)-4-(2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4- yl)pyridin-2(1H)-one 445.1 121

1-((S)-1-(4-chloro-3-fluorophenyl)-2- hydroxyethyl)-4-(2-(((3R,4R)-3-fluorotetrahydro-2H-pyran-4- yl)amino)pyrimidin-4-yl)pyridin- 2(1H)-one463.1 122

1-((R)-1-(4-chloro-3-fluorophenyl)-2- hydroxyethyl)-4-(2-(((3S,4S)-3-fluorotetrahydro-2H-pyran-4- yl)amino)pyrimidin-4-yl)pyridin- 2(1H)-one463.1 123

1-((S)-1-(4-chloro-3-fluorophenyl)-2- hydroxyethyl)-4-(2-(((3R,4S)-3-fluorotetrahydro-2H-pyran-4- yl)amino)pyrimidin-4-yl)pyridin- 2(1H)-one463.1 124

1-((S)-1-(4-chloro-3-fluorophenyl)-2- hydroxyethyl)-4-(2-((2,2-dimethyltetrahydro-2H-pyran-4- yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one 473.1 125

1-((S)-1-(4-chloro-3-fluorophenyl)-2- hydroxyethyl)-4-(2-((2-methyltetrahydro-2H-pyran-4- yl)amino)pyrimidin-4-yl)pyridin- 2(1H)-one459.1 126

1-((S)-1-(4-chloro-3-fluorophenyl)-2- hydroxyethyl)-4-(2-(((S)-4-methoxybutan-2-yl)amino)pyrimidin- 4-yl)pyridin-2(1H)-one 447.1 127

(S)-1-(1-(4-chloro-3-fluorophenyl)-2-methoxyethyl)-4-(2-((tetrahydro-2H- pyran-4-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one 459.2 128

(R)-1-(1-(4-chloro-3-fluorophenyl)-3- hydroxypropyl)-4-(5-fluoro-2-((tetrahydro-2H-pyran-4- yl)amino)pyrimidin-4-yl)pyridin- 2(1H)-one477.1 129

1-(1-(4-chloro-2-fluorophenyl)-2- hydroxyethyl)-4-(2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4- yl)pyridin-2(1H)-one 445.1 130

1-(1-(5-chloro-2-fluorophenyl)-2- hydroxyethyl)-4-(2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4- yl)pyridin-2(1H)-one 445.1 131

1-(1-(3-fluoro-5-methoxyphenyl)-2- hydroxyethyl)-4-(2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4- yl)pyridin-2(1H)-one 441.2 132

1-(1-(2-fluoro-3-methoxyphenyl)-2- hydroxyethyl)-4-(2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4- yl)pyridin-2(1H)-one 441.2 133

1-(1-(2-fluoro-5-methoxyphenyl)-2- hydroxyethyl)-4-(2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4- yl)pyridin-2(1H)-one 441 134

1-(1-(4-chloro-3-fluorophenyl)ethyl)- 4-(2-(((S)-1-hydroxybutan-2-yl)amino)pyrimidin-4-yl)pyridin- 2(1H)-one 417.1 135

4-(2-hydroxy-1-(2-oxo-4-(2- ((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)pyridin- 1(2H)-yl)ethyl)-2- methoxybenzonitrile446.1 136

(S)-1-((4-chloro-3-fluorophenyl)(1- methyl-1H-pyrazol-4-yl)methyl)-4-(2-((tetrahydro-2H-pyran-4- yl)amino)pyrimidin-4-yl)pyridin- 2(1H)-one495.2 137

(R)-1-((4-chloro-3-fluorophenyl)(1- methyl-1H-pyrazol-4-yl)methyl)-4-(2-((tetrahydro-2H-pyran-4- yl)amino)pyrimidin-4-yl)pyridin- 2(1H)-one481.2 138

1-(1-(4-chloro-3-fluorophenyl)-2- hydroxyethyl)-4-(2-((2-chloro-4-fluorophenyl)amino)pyrimidin-4- yl)pyridin-2(1H)-one 489 139

1-(1-(4-chloro-3-fluorophenyl)-2- hydroxyethyl)-4-(2-((2-ethylpyrimidin-4-yl)amino)pyrimidin- 4-yl)pyridin-2(1H)-one 467.2 140

1-(1-(4-chloro-3-fluorophenyl)-2- hydroxyethyl)-4-(2-((6-methylpyridin-2-yl)amino)pyrimidin- 4-yl)pyridin-2(1H)-one 452.1 141

1-(1-(4-chloro-3-fluorophenyl)-2- hydroxyethyl)-4-(2-((2-cyclopropylpyrimidin-4- yl)amino)pyrimidin-4-yl)pyridin- 2(1H)-one 479.1142

1-(1-(4-chloro-3-fluorophenyl)ethyl)-4-(2-((4,4,4-trifluoro-1-hydroxybutan-2-yl)amino)pyrimidin-4-yl)pyridin- 2(1H)-one 471.1 143

1-((S)-1-(4-chloro-3-fluorophenyl)-2- hydroxyethyl)-4-(2-(pyrrolidin-3-ylamino)pyrimidin-4-yl)pyridin- 2(1H)-one 430.3 144

1-(4-methoxyphenethyl)-4-(2- ((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)pyridin- 2(1H)-one 407.2 145

1-(4-fluorophenethyl)-4-(2- ((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)pyridin- 2(1H)-one 395.2 146

1-(3-chlorophenethyl)-4-(2- ((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)pyridin- 2(1H)-one 411.2 147

1-(1-(4-chloro-3-fluorophenyl)-2- hydroxyethyl)-4-(2-((5-fluoro-6-methylpyridin-2-yl)amino)pyrimidin- 4-yl)pyridin-2(1H)-one 470.1 148

(S)-4-(2-(azetidin-3- ylamino)pyrimidin-4-yl)-1-(1-(4-chloro-3-fluorophenyl)-2- hydroxyethyl)pyridin-2(1H)-one 416.2 149

1-(4-chlorophenethyl)-4-(2- ((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)pyridin- 2(1H)-one 411.2 150

1-(4-methylphenethyl)-4-(2- ((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)pyridin- 2(1H)-one 391.2 151

1-(3-methoxyphenethyl)-4-(2- ((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)pyridin- 2(1H)-one 407.3 152

1-(1-(4-chloro-3-fluorophenyl)-2- hydroxyethyl)-4-(2-(piperidin-3-ylamino)pyrimidin-4-yl)pyridin- 2(1H)-one 444.2 153

1-((1H-indol-5-yl)methyl)-4-(2- ((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)pyridin- 2(1H)-one 402.3 154

4-(2-((tetrahydro-2H-pyran-4- yl)amino)pyrimidin-4-yl)-1-(4-(trifluoromethyl)phenethyl)pyridin- 2(1H)-one 445.2 155

1-(3-methylphenethyl)-4-(2- ((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)pyridin- 2(1H)-one 391.3 156

4-(2-((tetrahydro-2H-pyran-4- yl)amino)pyrimidin-4-yl)-1-(3-(trifluoromethyl)phenethyl)pyridin- 2(1H)-one 445.2 157

4-(2-((tetrahydro-2H-pyran-4- yl)amino)pyrimidin-4-yl)-1-(4-(trifluoromethoxy)phenethyl)pyridin- 2(1H)-one 461.2 158

1-(1-(1H-indol-5-yl)ethyl)-4-(2- ((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)pyridin- 2(1H)-one 416.3 159

4-(2-((1-aminopropan-2- yl)amino)pyrimidin-4-yl)-1-(1-(4-chloro-3-fluorophenyl)-2- hydroxyethyl)pyridin-2(1H)-one 418.2 160

1-(1-(4-chloro-3-fluorophenyl)-2- hydroxyethyl)-4-(2-((5-cyclopropyl-1-methyl-1H-pyrazol-4- yl)amino)pyrimidin-4-yl)pyridin- 2(1H)-one 481.1161

(S)-4-(2-((5-bromo-2-methylpyridin- 4-yl)amino)pyrimidin-4-yl)-1-(1-(4-chloro-3-fluorophenyl)-2- hydroxyethyl)pyridin-2(1H)-one 529.93 162

1-(1-(4-chloro-3-fluorophenyl)-2- hydroxyethyl)-4-(2-(((cis)-2-(hydroxymethyl)tetrahydro-2H-pyran- 4-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one 475.1 163

1-(1-(4-chloro-3-fluorophenyl)-2- hydroxyethyl)-4-(2-((1,5-dimethyl-1H-pyrazol-4-yl)amino)pyrimidin-4- yl)pyridin-2(1H)-one 455.1 164

1-(1-(1H-indol-2-yl)ethyl)-4-(2- ((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)pyridin- 2(1H)-one 416.2 165

1-(3,4-dichlorophenethyl)-4-(2- ((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)pyridin- 2(1H)-one 445.1 166

1-(1-(4-chloro-3-fluorophenyl)-2- hydroxyethyl)-4-(2-,3-dimethyl-1H-pyrazol-4-yl)amino)pyrimidin-4- yl)pyridin-2(1H)-one 455.1 167

(S)-1-(1-(4-chloro-3-fluorophenyl)-2- hydroxyethyl)-4-(2-((1,3-dimethyl-1H-pyrazol-5-yl)amino)pyrimidin-4- yl)pyridin-2(1H)-one 455.13 168

(S)-1-(1-(4-chloro-3-fluorophenyl)-2- hydroxyethyl)-4-(2-((4-(2-hydroxypropan-2-yl)pyridin-2- yl)amino)pyrimidin-4-yl)pyridin- 2(1H)-one496.15 169

1-(1-(3-fluorophenyl)-2- hydroxyethyl)-4-(2-(((3S,4R)-3-fluorotetrahydro-2H-pyran-4- yl)amino)pyrimidin-4-yl)pyridin- 2(1H)-one429.2 170

4-(2-(2-oxo-4-(2-((tetrahydro-2H- pyran-4-yl)amino)pyrimidin-4-yl)pyridin-1(2H)-yl)ethyl)benzonitrile 402.3 171

1-(1-(1H-indol-6-yl)ethyl)-4-(2- ((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)pyridin- 2(1H)-one 416.3 172

1-(1-(4-chloro-3-fluorophenyl)vinyl)- 4-(2-((2-methylpyridin-4-yl)amino)pyrimidin-4-yl)pyridin- 2(1H)-one 434.1 173

(S)-1-(1-(4-chloro-3-fluorophenyl)-2- hydroxyethyl)-4-(2-((1-ethyl-3-methyl-1H-pyrazol-4- yl)amino)pyrimidin-4-yl)pyridin- 2(1H)-one 469.1174

1-((S)-1-(4-chloro-3-fluorophenyl)-2- hydroxyethyl)-4-(2-(((R)-1-(methylamino)propan-2- yl)amino)pyrimidin-4-yl)pyridin- 2(1H)-one 432.3175

1-((4-chloro-3-fluorophenyl)(1- methyl-1H-pyrazol-4-yl)methyl)-4-(2-(((3S,4R)-3-fluorotetrahydro-2H- pyran-4-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one 513.2 176

(S)-1-(1-(4-chloro-3-fluorophenyl)-2- hydroxyethyl)-4-(2-((1,5-dimethyl-1H-pyrazol-4-yl)amino)pyrimidin-4- yl)pyridin-2(1H)-one 455.1 177

1-(3-fluorophenethyl)-4-(2- ((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)pyridin- 2(1H)-one 395.1 178

1-((4-chloro-3-fluorophenyl)(1- methyl-1H-pyrazol-4-yl)methyl)-4-(2-(((cis)-2-(hydroxymethyl)tetrahydro- 2H-pyran-4-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one 547.2 (+Na) 179

(S)-1-(1-(4-chloro-3-fluorophenyl)-2- hydroxyethyl)-4-(2-((5-ethoxy-2-methylpyridin-4-yl)amino)pyrimidin- 4-yl)pyridin-2(1H)-one 496.2 180

4-(2-((tetrahydro-2H-pyran-4- yl)amino)pyrimidin-4-yl)-1-(3-(trifluoromethoxy)phenethyl)pyridin- 2(1H)-one 461.1 181

1-((S)-1-(4-chloro-3-fluorophenyl)-2- hydroxyethyl)-4-(2-(((S)-1-(methylamino)propan-2- yl)amino)pyrimidin-4-yl)pyridin- 2(1H)-one 432.2182

(S)-1-(1-(4-chloro-3-fluorophenyl)-2- hydroxyethyl)-4-(2-((1,3-dimethyl-1H-pyrazol-4-yl)amino)pyrimidin-4- yl)pyridin-2(1H)-one 455.13 183

(S)-1-(1-(3-chloro-4-fluorophenyl)-2- hydroxyethyl)-4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4- yl)pyridin-2(1H)-one 441.12 184

(S)-1-(1-(4-chloro-3-fluorophenyl)-2-hydroxyethyl)-4-(2-((1-isopropyl-1H- pyrazol-4-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one 469.1 185

(S)-1-(1-(4-chloro-3-fluorophenyl)-2- hydroxyethyl)-4-(2-((4-methyl-1H-imidazol-5-yl)amino)pyrimidin-4- yl)pyridin-2(1H)-one 441.1 186

(S)-1-(1-(4-chloro-3-fluorophenyl)-2- hydroxyethyl)-4-(2-((1-methyl-1H-imidazol-5-yl)amino)pyrimidin-4- yl)pyridin-2(1H)-one 441.12 187

(S)-1-(1-(4-chloro-3-fluorophenyl)-2- hydroxyethyl)-4-(2-((1-ethyl-1H-pyrazol-4-yl)amino)pyrimidin-4- yl)pyridin-2(1H)-one 455.13 188

(S)-1-(1-(4-chloro-3-fluorophenyl)-2- hydroxyethyl)-4-(2-((2-(2-hydroxypropan-2-yl)pyridin-4- yl)amino)pyrimidin-4-yl)pyridin- 2(1H)-one496.2 189

(S)1-(1-(3-chloro-4-fluorophenyl)-2- hydroxyethyl)-4-(2-((2-methyl-2,4,5,6- tetrahydrocyclopenta[c]pyrazol-3-yl)amino)pyrimidin-4-yl)pyridin- 2(1H)-one 481.1 190

(S)-5-((4-(1-(1-(3-chloro-4- fluorophenyl)-2-hydroxyethyl)-2-oxo-1,2-dihydropyridin-4-yl)pyrimidin-2- yl)amino)-1-methyl-1H-pyrazole-4-carbonitrile 466 191

1-((3,4-dichlorophenyl)(1-methyl-1H- pyrazol-4-yl)methyl)-4-(2-((tetrahydro-2H-pyran-4- yl)amino)pyrimidin-4-yl)pyridin- 2(1H)-one513.2 192

(S)-1-(1-(3-chloro-4-fluorophenyl)-2- hydroxyethyl)-4-(2-((3-methylpyridin-4-yl)amino)pyrimidin- 4-yl)pyridin-2(1H)-one 452.1 193

1-((4-chloro-3-fluorophenyl)(1- methyl-1H-pyrazol-4-yl)methyl)-4-(2-(((3S,4S)-3-fluorotetrahydro-2H- pyran-4-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one 513.2 194

1-(1-(4-chloro-3-fluorophenyl)-2- hydroxyethyl)-4-(2-((4-fluoro-2-methylphenyl)amino)pyrimidin-4- yl)pyridin-2(1H)-one 469.1 195

1-((1H-indazol-6-yl)methyl)-4-(2- ((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)pyridin- 2(1H)-one 403.1 196

1-((3-fluorophenyl)(1-methyl-1H- pyrazol-4-yl)methyl)-4-(2-((tetrahydro-2H-pyran-4- yl)amino)pyrimidin-4-yl)pyridin- 2(1H)-one461.2 197

1-((1H-indol-7-yl)methyl)-4-(2- ((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)pyridin- 2(1H)-one 402.2 198

1-((4-chloro-3-fluorophenyl)(1- methyl-1H-pyrazol-4-yl)methyl)-4-(2-((2-methylpyridin-4- yl)amino)pyrimidin-4-yl)pyridin- 2(1H)-one 502.1199

1-(benzo[d]thiazol-2-ylmethyl)-4-(2- ((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)pyridin- 2(1H)-one 420.1 200

1-((1H-indol-4-yl)methyl)-4-(2- ((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)pyridin- 2(1H)-one 402.2 201

1-((4-chloro-3-fluorophenyl)(1- methyl-1H-pyrazol-4-yl)methyl)-4-(5-fluoro-2-(((cis)-2- (hydroxymethyl)tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)pyridin- 2(1H)-one 565.2 (+Na) 202

(S)-1-(1-(4-chloro-3-fluorophenyl)-2- hydroxyethyl)-4-(2-((1-ethyl-3-methyl-1H-pyrazol-5- yl)amino)pyrimidin-4-yl)pyridin- 2(1H)-one 469.1203

(S)-1-(1-(4-chloro-3-fluorophenyl)-2- hydroxyethyl)-4-(2-((1,4-dimethyl-1H-pyrazol-5-yl)amino)pyrimidin-4- yl)pyridin-2(1H)-one 455.1 204

(S)-1-(1-(3-chloro-4-fluorophenyl)-2- hydroxyethy))-4-(2-((1-ethyl-1H-pyrazol-5-yl)amino)pyrimidin-4- yl)pyridin-2(1H)-one 455.1 205

(S)-1-(1-(3-chloro-4-fluorophenyl)-2-hydroxyethyl)-4-(2-((3-isopropyl-1- methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)pyridin- 2(1H)-one 483.2 206

(S)-1-(1-(3-chloro-4-fluorophenyl)-2- hydroxyethyl)-4-(2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4- yl)pyridin-2(1H)-one 441.1 207

(S)-1-(1-(3-chloro-4-fluorophenyl)-2- hydroxyethyl)-4-(2-((1,3-dimethyl-1H-pyrazol-5-yl)amino)pyrimidin-4- yl)pyridin-2(1H)-one 455.1 208

(S)-1-(1-(3-chloro-4-fluorophenyl)-2- hydroxyethyl)-4-(2-((3-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4- yl)pyridin-2(1H)-one 441.12 209

1-((3,4-dichlorophenyl)(1-methyl-1H- pyrazol-4-yl)methyl)-4-(5-fluoro-2-((tetrahydro-2H-pyran-4- yl)amino)pyrimidin-4-yl)pyridin- 2(1H)-one 531210

1-((3-chloro-1H-indol-6-yl)methyl)-4- (2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)pyridin- 2(1H)-one 436.2 211

1-(indolin-6-ylmethyl)-4-(2- ((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)pyridin- 2(1H)-one 404.2 212

1-((4-chloro-3-fluorophenyl)(1- methyl-1H-pyrazol-4-yl)methyl)-4-(2-((1,3-dimethyl-1H-pyrazol-4- yl)amino)pyrimidin-4-yl)pyridin- 2(1H)-one505.2 213

1-((1-methyl-1H-benzo[d]imidazol-2- yl)methyl)-4-(2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4- yl)pyridin-2(1H)-one 417.2 214

1-(benzo[d]oxazol-2-ylmethyl)-4-(2- ((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)pyridin- 2(1H)-one 404.2 215

1-((R)-1-(3-fluorophenyl)-2- hydroxyethyl)-4-(2-(((3S,4R)-3-fluorotetrahydro-2H-pyran-4- yl)amino)pyrimidin-4-yl)pyridin- 2(1H)-one429.2 216

1-((S)-1-3-fluorophenyl)-2- hydroxyethyl)-4-(2-(((3S,4R)-3-fluorotetrahydro-2H-pyran-4- yl)amino)pyrimidin-4-yl)pyridin- 2(1H)-one429.2 217

(S)-1-(1-(4-chloro-3-fluorophenyl)-2- hydroxyethyl)-4-(2-((3-ethyl-1-methyl-1H-pyrazol-4- yl)amino)pyrimidin-4-yl)pyridin- 2(1H)-one 469.2218

(S)-1-(1-(4-chloro-3-fluorophenyl)-2-hydroxyethyl)-4-(2-((1,3,5-trimethyl- 1H-pyrazol-4-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one 469.2 219

(S)-1-(1-(4-chloro-3-fluorophenyl)-2- hydroxyethyl)-4-(2-((3,5-dimethyl-1H-pyrazol-4-yl)amino)pyrimidin-4- yl)pyridin-2(1H)-one 455.2 220

(S)-1-((4-chloro-3-fluorophenyl)(1- methyl-1H-pyrazol-4-yl)methyl)-4-(5-fluoro-2-((tetrahydro-2H-pyran-4- yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one 513.1 221

(R)-1-((4-chloro-3-fluorophenyl)(1- methyl-1H-pyrazol-4-yl)methyl)-4-(5-fluoro-2-((tetrahydro-2H-pyran-4- yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one 513.1 222

1-((S)-1-(3-chlorophenyl)-2- hydroxyethyl)-4-(2-(((cis)-3-hydroxycyclobutyl)amino)pyrimidin- 4-yl)pyridin-2(1H)-one 413.1 223

1-((S)-1-(3-chlorophenyl)-2- hydroxyethyl)-4-(2-(((trans)-3-hydroxycyclobutyl)amino)pyrimidin- 4-yl)pyridin-2(1H)-one 413.1 224

1-((5-chlorobenzo[d]oxazol-2- yl)methyl)-4-(2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4- yl)pyridin-2(1H)-one 438.1 225

(S)-1-(1-(3-chlorophenyl)-2- hydroxyethyl)-4-(2-((3-methoxycyclobutyl)amino)pyrimidin- 4-yl)pyridin-2(1H)-one 427.1 226

1-((5-chloro-1H-indol-2-yl)methyl)-4- (2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)pyridin- 2(1H)-one 436 227

(S)-1-(1-(4-chloro-3-fluorophenyl)-2-hydroxyethyl)-4-(2-((2-cyclopropyl-5- methoxypyridin-4-yl)amino)pyrimidin-4-yl)pyridin- 2(1H)-one 508.1 228

(S)-1-(1-(4-chloro-3-fluorophenyl)-2- hydroxyethyl)-4-(2-((5-ethyl-1-methyl-1H-pyrazol-4- yl)amino)pyrimidin-4-yl)pyridin- 2(1H)-one 469.2229

1-((3-methyl-1H-indol-6-yl)methyl)- 4-(2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)pyridin- 2(1H)-one 416.3 230

1-((1-methyl-1H-indol-6-yl)methyl)- 4-(2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)pyridin- 2(1H)-one 416.2 231

1-((5-fluoro-1H-indol-2-yl)methyl)-4- (2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)pyridin- 2(1H)-one 420.3 232

1-((1H-indol-3-yl)methyl)-4-(2- ((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)pyridin- 2(1H)-one 402.3 233

1-((1H-pyrrolo[2,3-c]pyridin-2- yl)methyl)-4-(2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4- yl)pyridin-2(1H)-one 403.2 234

1-((6-chlorobenzo[d]oxazol-2- yl)methyl)-4-(2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4- yl)pyridin-2(1H)-one 438.1 235

(S)-1-(1-(3-fluorophenyl)-2- hydroxyethyl)-4-(2-((3-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4- yl)pyridin-2(1H)-one 407.3 236

1-((1H-benzo[d]imidazol-2- yl)methyl)-4-(2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4- yl)pyridin-2(1H)-one 403.2 237

1-((2-methyl-1H-indol-6-yl)methyl)- 4-(2-((telrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)pyridin- 2(1H)-one 416.1 238

1-((7-fluoro-1H-indol-2-yl)methyl)-4- (2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)pyridin- 2(1H)-one 420.1 239

(S)-4-((4-(1-(1-(4-chloro-3- fluorophenyl)-2-hydroxyethyl)-2-oxo-1,2-dihydropyridin-4-yl)pyrimidin-2- yl)amino)-2-methoxypyridine 1-oxide484.1 240

(S)-1-(1-(4-chloro-3-fluorophenyl)-2- hydroxyethyl)-4-(2-((5-methoxy-2-methylpyridin-4-yl)amino)pyrimidin- 4-yl)pyridin-2(1H)-one 482.2 241

(S)-1-(1-(4-chloro-3-fluorophenyl)-2- hydroxyethyl)-4-(2-((3-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4- yl)pyridin-2(1H)-one 441.2 242

1-((2,3-dimethyl-1H-indol-6- yl)methyl)-4-(2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4- yl)pyridin-2(1H)-one 430.1 243

1-((3-methyl-1H-indol-2-yl)methyl)- 4-(2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)pyridin- 2(1H)-one 416.2 244

1-(1-(3-fluorophenyl)-2- hydroxyethyl)-4-(2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4- yl)pyridin-2(1H)-one 407.2 245

(S)-1-(1-(4-chloro-3-fluorophenyl)-2-hydroxyethyl)-4-(2-((5-methyl-1,3,4- oxadiazol-2-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one 443.2 246

1-((3-chloro-1H-indol-2-yl)methyl)-4- (2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)pyridin- 2(1H)-one 436.1 247

1-((2-methyl-1H-indol-3-yl)methyl)- 4-(2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)pyridin- 2(1H)-one 416.2 248

1-(1-(3-fluorophenyl)-2- hydroxyethyl)-4-(2-(((3S,4S)-3-fluorotetrahydro-2H-pyran-4- yl)amino)pyrimidin-4-yl)pyridin- 2(1H)-one429.3 249

(S)-1-(1-(4-chloro-3-fluorophenyl)-2- hydroxyethyl)-4-(2-((3-ethyl-1-methyl-1H-pyrazol-5- yl)amino)pyrimidin-4-yl)pyridin- 2(1H)-one 469.1250

1-((6-chloro-1H-indol-2-yl)methyl)-4- (2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)pyridin- 2(1H)-one 436.1 251

1-(1-(4-chloro-3-methoxyphenyl)-2- hydroxyethyl)-4-(2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4- yl)pyridin-2(1H)-one 457.1 252

(S)-1-(1-(4-chloro-3-fluorophenyl)-2- hydroxyethyl)-4-(2-((1-(2-hydroxyethyl)-3-methyl-1H-pyrazol- 4-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one 485.2 253

(S)-1-(1-(4-chloro-3-fluorophenyl)-2- hydroxyethyl)-4-(2-((1-(2-hydroxyethyl)-5-methyl-1H-pyrazol- 4-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one 485.3 254

(S)-1-(1-(4-chloro-3-fluorophenyl)-2- hydroxyethyl)-4-(2-((1-methyl-3-(trifluoromelhyl)-1H-pyrazol-4- yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one 509.1 255

(S)-1-(1-(4-chloro-3-fluorophenyl)-2 hydroxyethyl)-4-(2-((1-methyl-3-(trifluoromethyl)-1H-pyrazol-5- yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one 509.1 256

1-((3-cyclopropyl-1H-indol-6- yl)methyl)-4-(2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4- yl)pyridin-2(1H)-one 442.2 257

1-((6-fluoro-1H-indol-2-yl)methyl)-4- (2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)pyridin- 2(1H)-one 420.1 258

1-(1-(5-fluoro-1H-indol-2-yl)ethyl)-4- (2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)pyridin- 2(1H)-one 434.2 259

(S)-1-(1-(3-fluorophenyl)-2- hydroxyethyl)-4-(2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4- yl)pyridin-2(1H)-one 407.1 260

(R)-1-(1-(3-fluorophenyl)-2- hydroxyethyl)-4-(2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4- yl)pyridin-2(1H)-one 406 261

(S)-1-(1-(4-chloro-3-fluorophenyl)-2- hydroxyethyl)-4-(2-((1-methyl-1H-1,2,3-triazol-5-yl)amino)pyrimidin-4- yl)pyridin-2(1H)-one 442.2 262

(S)-1-(1-(4-chIoro-3-fluorophenyl)-2- hydroxyethyl)-4-(5-fluoro-2-((2-methylpyridin-4-yl)amino)pyrimidin- 4-yl)pyridin-2(1H)-one 470.2 263

(S)-1-(1-(4-chloro-3-fluorophenyl)-2- hydroxyethyl)-4-(5-fluoro-2-((3-methylpyridin-4-yl)amino)pyrimidin- 4-yl)pyridin-2(1H)-one 470.1 264

(S)-1-(1-(4-chloro-3-fluorophenyl)-2- hydroxyethyl)-4-(5-fluoro-2-((1-methyl-1H-pyrazol-5- yl)amino)pyrimidin-4-yl)pyridin- 2(1H)-one 459.1265

1-((1H-benzo[d]imidazol-6- yl)methyl)-4-(2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4- yl)pyridin-2(1H)-one 403.2 266

1-((4-fluoro-1H-indol-2-yl)methyl)-4- (2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)pyridin- 2(1H)-one 420.1 267

(S)-4-(5-fluoro-2-((2-methylpyridin-4- yl)amino)pyrimidin-4-yl)-1-(1-(3-fluorophenyl)-2- hydroxyethyl)pyridin-2(1H)-one 436.2 268

(S)-4-(5-fluoro-2-((3-methylpyridin-4- yl)amino)pyrimidin-4-yl)-1-(1-(3-fluorophenyl)-2- hydroxyethyl)pyridin-2(1H)-one 436.2 269

1-(1-(4-chloro-3-fluorophenyl)vinyl)- 4-(2-((1-(2-hydroxyethyl)-1H-pyrazol-5-yl)amino)pyrimidin-4- yl)pyridin-2(1H)-one 453.1 270

(S)-methyl 4-((4-(1-(1-(4-chloro-3- fluorophenyl)-2-hydroxyethyl)-2-oxo-1,2-dihydropyridin-4-yl)pyrimidin-2- yl)amino)picolinate 496.1 271

(S)-4-((4-(1-(1-(4-chloro-3- fluorophenyl)-2-hydroxyethyl)-2-oxo-1,2-dihydropyridin-4-yl)pyrimidin-2- yl)amino)picolinic acid 482.1 272

(S)-1-(1-(4-chlorophenyl)-2- hydroxyethyl)-4-(5-fluoro-2-((2-methylpyridin-4-yl)amino)pyrimidin- 4-yl)pyridin-2(1H)-one 445.1 273

(S)-1-(1-(4-chlorophenyl)-2- hydroxyethyl)-4-(5-fluoro-2-((3-methylpyridin-4-yl)amino)pyrimidin- 4-yl)pyridin-2(1H)-one 452.1 274

(S)-1-(1-(4-chloro-3-fluorophenyl)-2-hydroxyethyl)-4-(2-((1-cyclopropyl-5- methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)pyridin- 2(1H)-one 481.1 275

(S)-1-(1-(4-chloro-3-fluorophenyl)-2-hydroxyethyl)-4-(2-((1-cyclopropyl-3- methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)pyridin- 2(1H)-one 481.1 276

1-((S)-(4-chloro-3-fluorophenyl)(1- methyl-1H-pyrazol-4-yl)methyl)-4-(2-(((1S,3S)-3- hydroxycyclopentyl)amino)pyrimidin- 4-yl)pyridin-2(1H)-one495.1 277

(S)-1-(1-(4-chloro-3-fluorophenyl)-2- hydroxyethyl)-4-(2-((2,3-dimethylpyridin-4- yl)amino)pyrimidin-4-yl)pyridin- 2(1H)-one 466.1 278

(S)-1-(1-(4-chloro-3-fluorophenyl)-2- hydroxyethyl)-4-(2-((2,5-dimethylpyridin-4- yl)amino)pyrimidin-4-yl)pyridin- 2(1H)-one 466.1 279

1-((4-chloro-3-fluorophenyl)(1- methyl-1H-pyrazol-4-yl)methyl)-4-(2-((1,3-dimethyl-1H-pyrazol-4- yl)amino)-5-fluoropyrimidin-4-yl)pyridin-2(1H)-one 505.2 280

4-(5-fluoro-2-((tetrahydro-2H-pyran- 4-yl)amino)pyrimidin-4-yl)-1-((3-fluorophenyl)(1-methyl-1H-pyrazol- 4-yl)methyl)pyridin-2(1H)-one 513.1281

1-((7-fluoro-1H-indol-6-yl)methyl)-4- (2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)pyridin- 2(1H)-one 420.1 282

1-((4-chloro-3-fluorophenyl)(1- methyl-1H-pyrazol-4-yl)methyl)-4-(5-fluoro-2-(((3S,4R)-3-fluorotetrahydro- 2H-pyran-4-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one 283

1-((4-chlorophenyl)(1-methyl-1H- pyrazol-4-yl)methyl)-4-(5-fluoro-2-((tetrahydro-2H-pyran-4- yl)amino)pyrimidin-4-yl)pyridin- 2(1H)-one 284

(S)-4-(2-((1,3,4-oxadiazol-2- yl)amino)pyrimidin-4-yl)-1-(1-(4-chloro-3-fluorophenyl)-2- hydroxyethyl)pyridin-2(1H)-one 429.1 285

1-(1-(4-chloro-3-fluorophenyl)-3- hydroxy-3-methylbutyl)-4-(2-((tetrahydro-2H-pyran-4- yl)amino)pyrimidin-4-yl)pyridin- 2(1H)-one487.2 286

(S)-1-(1-(4-chloro-3-fluorophenyl)-2- hydroxyethyl)-4-(2-((3-methylpyridazin-4- yl)amino)pyrimidin-4-yl)pyridin- 2(1H)-one 453.1 287

(S)-1-(1-(4-chloro-3-fluorophenyl)-2- hydroxyethyl)-4-(2-(pyridazin-4-ylamino)pyrimidin-4-yl)pyridin- 2(1H)-one 439.0 288

1-((S)-(4-chloro-3-fluorophenyl)((R)- pyrrolidin-3-yl)methyl)-4-(2-((tetrahydro-2H-pyran-4- yl)amino)pyrimidin-4-yl)pyridin- 2(1H)-one m/z(APCI- M + 1 = 484.2, 486.1 289

1-((4-fluoro-1H-indol-6-yl)methyl)-4- (2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)pyridin- 2(1H)-one 420.0 290

(S)-2-(4-chloro-3-fluorophenyl)-2-(2- oxo-4-(2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)pyridin- 1(2H)-yl)ethyl 2-amino-2-methylpropanoate 530.2 291

(S)-1-(1-(5-fluoro-1H-indol-2-yl)-2- hydroxyethyl)-4-(2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4- yl)pyridin-2(1H)-one 450.2 292

(R)-1-(1-(4-chloro-3-fluorophenyl)-3- hydroxypropyl)-4-(2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4- yl)pyridin-2(1H)-one 455.1 293

(S)-2-(4-chloro-3-fluorophenyl)-2-(4- (2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)-2- oxopyridin-1(2H)-yl)ethyl acetate 483.1 294

1-((5-fluoro-1H-indol-6-yl)methyl)-4- (2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)pyridin- 2(1H)-one 420.3 295

1-(1-(4-chloro-3-fluorophenyl)vinyl)- 4-(2-((1-ethyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)pyridin- 2(1H)-one 437.1 296

(S)-1-(1-(4-chloro-3-fluorophenyl)-2- hydroxyethyl)-4-(2-((1-ethyl-1H-pyrazol-5-yl)amino)pyrimidin-4- yl)pyridin-2(1H)-one 455.1 297

1-(4-methoxybenzyl)-4-(2-((1-methyl- 1H-pyrazol-5-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one 389.2 298

1-(3-fluoro-4-methoxybenzyl)-4-(2- ((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)pyridin- 2(1H)-one 407.2 299

1-(1-(4-fluoro-3-methoxyphenyl)-2- hydroxyethyl)-4-(2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4- yl)pyridin-2(1H)-one 437.3 300

1-(1-(4-chloro-3-methoxyphenyl)-2- hydroxyethyl)-4-(2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4- yl)pyridin-2(1H)-one 453.3 301

(S)-4-(2-((2H-tetrazol-5- yl)amino)pyrimidin-4-yl)-1-(1-(4-chloro-3-fluorophenyl)-2- hydroxyethyl)pyridin-2(1H)-one 429.2 302

(S)-1-(1-(4-chloro-3-fluorophenyl)-2- hydroxyethyl)-4-(2-((1-methyl-1H-tetrazol-5-yl)amino)pyrimidin-4- yl)pyridin-2(1H)-one 443.1 303

1-((1R,3R)-1-(4-chloro-3- fluorophenyl)-3-hydroxybutyl)-4-(2-((1-methyl-1H-pyrazol-5- yl)amino)pyrimidin-4-yl)pyridin- 2(1H)-one469.3 304

1-((1S,3R)-1-(4-chloro-3- fluorophenyl)-3-hydroxybutyl)-4-(2-((1-methyl-1H-pyrazol-5- yl)amino)pyrimidin-4-yl)pyridin- 2(1H)-one469.3 305

(S)-1-(2-amino-1-(4-chloro-3- fluorophenyl)ethyl)-4-(2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4- yl)pyridin-2(1H)-one 444.2 306

1-benzyl-4-(2-((tetrahydro-2H-pyran- 4-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one 363.2 307

1-(3-chlorobenzyl)-4-(2-((tetrahydro- 2H-pyran-4-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one 397.2 308

1-(4-chlorobenzyl)-4-(2-((tetrahydro- 2H-pyran-4-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one 397.2 309

1-(4-chloro-3-fluorobenzyl)-4-(2- ((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)pyridin- 2(1H)-one 415.2 310

1-(3-chloro-4-fluorobenzyl)-4-(2- ((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)pyridin- 2(1H)-one 415.2 311

1-(1-(4-chloro-3-fluorophenyl)-2- hydroxyethyl)-4-(2-((3-cyclopropyl-1-methyl-1H-pyrazol-4- yl)amino)pyrimidin-4-yl)pyridin- 2(1H)-one 481.1312

(S)-1-(1-(4-chloro-3-fluorophenyl)-2- hydroxyethyl)-4-(2-((3-(hydroxymethyl)pyridin-4- yl)amino)pyrimidin-4-yl)pyridin- 2(1H)-one468.1 313

(S)-2-((4-(1-(1-(4-chloro-3- fluorophenyl)-2-hydroxyethyl)-2-oxo-1,2-dihydropyridin-4-yl)pyrimidin-2- yl)amino)pyrimidin-4(3H)-one 455314

(S)-4-(2-((1H-pyrazol-3- yl)amino)pyrimidin-4-yl)-1-(1-(4-chloro-3-fluorophenyl)-2- hydroxyethyl)pyridin-2(1H)-one 427.1 315

(S)-1-(1-(4-chloro-3-fluorophenyl)-2-hydroxyethyl)-4-(2-((3-methyloxetan- 3-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one 431.1 316

(S)-1-(1-(3-chloro-4-fluorophenyl)-2- hydroxyethyl)-4-(2-((4-methyl-1H-imidazol-2-yl)amino)pyrimidin-4- yl)pyridin-2(1H)-one 441.1 317

(S)-1-(1-(4-chloro-3-fluorophenyl)-2- hydroxyethyl)-4-(2-((3-(hydroxymethyl)-1-methyl-1H- pyrazol-4-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one 471.1 318

(S)-1-(1-(4-chloro-3-fluorophenyl)-2- hydroxyethyl)-4-(2-((1-methyl-1H-imidazol-2-yl)amino)pyrimidin-4- yl)pyridin-2(1H)-one 441.1 319

(S)-1-(1-(4-chloro-3-fluorophenyl)-2- hydroxyethyl)-4-(2-((3,5-dimethylpyridin-4- yl)amino)pyrimidin-4-yl)pyridin- 2(1H)-one 466.1 320

(S)-1-(1-(4-chloro-3-fluorophenyl)-2- hydroxyethyl)-4-(2-((3-(trifluoromethyl)-1H-pyrazol-5- yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one 495.1 321

(S)-1-(1-(4-chloro-3-fluorophenyl)-2- hydroxyethyl)-4-(2-((3-hydroxypyridin-4- yl)amino)pyrimidin-4-yl)pyridin- 2(1H)-one 454.1 322

(S)-1-(1-(4-chloro-3-fluorophenyl)-2- hydroxyethyl)-4-(2-((2-oxo-1,2-dihydropyridin-4-yl)amino)pyrimidin 4-yl)pyridin-2(1H)-one 454.1 323

(S)-1-(1-(4-chloro-3-fluorophenyl)-2- hydroxyethyl)-4-(2-((1-(2-hydroxyethyl)-1H-pyrazol-5- yl)amino)pyrimidin-4-yl)pyridin- 2(1H)-one471.1

Example α

(S)-2-(4-chloro-3-fluorophenyl)-2-(2-oxo-4-(2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)pyridin-1(2H)-yl)ethyl dihydrogen phosphate

Step A:1-[(1S)-1-(4-Chloro-3-fluoro-phenyl)-2-hydroxy-ethyl]-4-[2-(tetrahydropyran-4-ylamino)pyrimidin-4-yl]pyridin-2-one(0.62 g, 1.39 mmol) was transferred to a dry 100 mL round bottom flaskin THF (50 mL). Cesium carbonate (2.26 g, 6.93 mmol) was added. Themixture was stirred at room temperature for 20 minutes before addingdibenzylphosphoryl chloride (0.91 g, 3.05 mmol) in toluene. The mixturewas left to stir overnight at room temperature. The mixture was dilutedwith ethyl acetate and washed with water (2×30 mL), saturated sodiumbicarbonate (2×30 mL) and brine (2×30 mL), and then dried over sodiumsulfate. The solvent was removed to leave an oil. The oil was purifiedby CombiFlash (24 g column; 0-5% methanol/DCM over 15 minutes). LCMSconfirmed product to be (S)-dibenzyl(2-(4-chloro-3-fluorophenyl)-2-(2-oxo-4-(2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)pyridin-1(2H)-yl)ethyl)phosphate (978 mg). (M+1=705).

Step B: 5% Pd/C (0.15 g) was added to (S)-dibenzyl(2-(4-chloro-3-fluorophenyl)-2-(2-oxo-4-(2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)pyridin-1(2H)-yl)ethyl)phosphate(978 mg) under nitrogen. MeOH (8 mL) was added, and the mixture waspurged with a hydrogen balloon. The mixture was left under hydrogenovernight. The mixture was filtered through Celite®, and the solvent wasremoved to leave a solid. The solid was purified by HPLC to obtain(S)-2-(4-chloro-3-fluorophenyl)-2-(2-oxo-4-(2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)pyridin-1(2H)-yl)ethyldihydrogen phosphate (3.8 mg). MS=525.0.

Example β

(S)-(2-(4-chloro-3-fluorophenyl)-2-(2-oxo-4-(2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)pyridin-1(2H)-yl)ethoxy)methyl dihydrogen phosphate

Step A: Sodium hydride (44 mg, 1.10 mmol) was added to1-[(1S)-1-(4-chloro-3-fluorophenyl)-2-hydroxyethyl]-4-[2-(tetrahydropyran-4-ylamino)pyrimidin-4-yl]pyridine-2-one(0.49 g, 1.10 mmol) in DMF (10 mL) at 0° C., which was left to stir at0° C. In a separate vial, sodium iodide (0.17 g, 1.10 mmol) andchlorodimethyl sulfide (0.11 g, 1.10 mmol) were transferred, which wasthen added to the reaction mixture. The reaction mixture was stirredovernight at room temperature. The mixture was quenched carefully withwater before diluting with ethyl acetate. The phases were separated. Theorganic phase was washed with saturated sodium bicarbonate, water, andfollowed by brine. The mixture was dried over sodium sulfate beforeremoving the solvent to leave an oil. The oil was purified by CombiFlash(24 g column, 0-10% MeOH/DCM over 20 minutes) to furnish(S)-1-(1-(4-chloro-3-fluorophenyl)-2-((methylthio)methoxy)ethyl)-4-(2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one(555 mg) as a solid (M+1=506).

Step B: Phosphoric acid (0.40 g, 3.98 mmol), 4 Å molecular sieves (5 g)and N-iodosuccinimide (0.46 g, 1.99 mmol) were added to(S)-1-(1-(4-chloro-3-fluorophenyl)-2-((methylthio)methoxy)ethyl)-4-(2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one(0.50 g, 1.00 mmol) in DMF (5 mL). The mixture was stirred at roomtemperature for 2 hours. The mixture was quenched with sodiumthiosulfate. Sodium carbonate was added to bring pH to 10, and thesolvent was removed. The resultant was purified by HPLC to afford(S)-(2-(4-chloro-3-fluorophenyl)-2-(2-oxo-4-(2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)pyridin-1(2H)-yl)ethoxy)methyldihydrogen phosphate (13 mg). M+1=555.1.

It will be understood that the enumerated embodiments are not intendedto limit the invention to those embodiments. On the contrary, theinvention is intended to cover all alternatives, modifications andequivalents, which may be included within the scope of the presentinvention as defined by the claims. Thus, the foregoing description isconsidered as illustrative only of the principles of the invention.

What is claimed is:
 1. A compound selected from Formula I:

or a stereoisomer, tautomer, prodrug or pharmaceutically acceptable saltthereof, wherein: X₁ is selected from CH and N; X₂ is selected from CR⁵and N; Y₁ is selected from CR⁶ and N; Y₂ is selected from CR⁷ and N; R¹is selected from (a) C₁-C₆ alkyl optionally substituted with one or moregroups independently selected from halogen, OR^(a), NR^(b)R^(c), oxo,CN, C₃-C₆ cycloalkyl and a 3 to 7 membered heterocycle, (b) C₃-C₇cycloalkyl optionally substituted with one or more groups independentlyselected from halogen, OR^(a), CN and C₁-C₃ alkyl optionally substitutedwith one or more groups independently selected from halogen and OR^(d),(c) phenyl optionally substituted with one or more groups independentlyselected from halogen, OR^(a), CN, C₃-C₆ cycloalkyl and C₁-C₃ alkyloptionally substituted with one or more groups independently selectedfrom halogen and OR^(d), (d) a 3 to 7 membered saturated or partiallyunsaturated heterocycle optionally substituted with one or more groupsindependently selected from halogen, OR^(a), oxo, CN, C₃-C₆ cycloalkyland C₁-C₃ alkyl optionally substituted with one or more groupsindependently selected from halogen and OR^(d), (e) a 5 to 6 memberedheteroaryl optionally substituted with one or more groups independentlyselected from halogen, OR^(e), oxide, CN, C₃-C₆ cycloalkyl and C₁-C₃alkyl optionally substituted with one or more groups independentlyselected from halogen, oxo and OR^(d), and (f) a 7 to 10 memberedbicyclic heterocycle optionally substituted with one or more groupsindependently selected from halogen, OR^(a), oxo, CN, C₃-C₆ cycloalkyland C₁-C₃ alkyl optionally substituted with one or more groupsindependently selected from halogen and OR^(d); R² is selected from (a)hydrogen, (b) C₁-C₆ alkyl optionally substituted with one or more groupsselected from OR^(f), oxo, NH₂, NH(C₁-C₃ alkyl) and N(C₁-C₃ alkyl)₂, (c)C₁-C₆ alkenyl optionally substituted with one or more groups selectedfrom OR^(f), oxo, NH₂, NH(C₁-C₃ alkyl) and N(C₁-C₃ alkyl)₂, (d) C₁-C₆alkynyl optionally substituted with one or more groups selected fromOR^(f), oxo, NH₂, NH(C₁-C₃ alkyl) and N(C₁-C₃ alkyl)₂, (e) C₃-C₆cycloalkyl optionally substituted with one or more groups selected fromOR^(f) and R^(g), (f) phenyl optionally substituted with one or moregroups selected from OR^(f) and R^(g), (g) a 3 to 7 membered heterocycleoptionally substituted with one or more groups selected from OR^(f) andR^(g), and (h) a 5 to 6 membered heteroaryl optionally substituted withone or more groups selected from OR^(f) and R^(g); R³ is selected from(a) (CR^(h)R^(i))_(x)-phenyl, wherein the phenyl may be optionallysubstituted with one or more R^(j) groups, (b) (CR^(h)R^(i))_(x)-(5 to 6membered heteroaryl), wherein the heteroaryl may be optionallysubstituted with one or more R^(j) groups, (c) (CR^(h)R^(i))_(x)-(9 to10 membered bicyclic heterocycle), wherein the heterocycle may beoptionally substituted with one or more R^(j) groups, and (d)(CR^(h)R^(i))_(x)-(9 to 10 membered bicyclic heteroaryl), wherein theheteroaryl may be optionally substituted with one or more R^(j) groups;each R⁴, R⁵, R⁶ and R⁷ is independently selected from hydrogen, halogenand C₁-C₃ alkyl; each R^(a), R^(b), R^(c), R^(d) and R^(e) areindependently selected from hydrogen and C₁-C₆ alkyl; R^(f) is selectedfrom hydrogen and C₁-C₆ alkyl optionally substituted with one or moregroups selected from oxo, NH₂, NH(C₁-C₃ alkyl) and N(C₁-C₃ alkyl)₂; eachR^(g) is C₁-C₆ alkyl; R^(h) and R^(i) are independently selected fromhydrogen, OR^(k) and C₁-C₆ alkyl optionally substituted with OR^(m);each R^(j) is independently selected from halogen, CN, cyclopropyl,C₁-C₆ alkyl optionally substituted with halogen, and C₁-C₆ alkoxyoptionally substituted with halogen; R^(k) and R^(m) are independentlyhydrogen or C₁-C₃ alkyl; and x is 0 or
 1. 2. A method of inhibiting ERKprotein kinase activity in a cell comprising treating the cell with acompound of claim
 1. 3. A method of inhibiting ERK protein kinaseactivity in a patient in need thereof comprising the step ofadministering to the patient a compound according to claim
 1. 4. Amethod of treating or ameliorating the severity of a hyperproliferativedisorder in a patient in need thereof comprising administering to thepatient a compound according to claim
 1. 5. A compound of Formula 10.1:

wherein: X₁ is selected from CH and N; X₂ is selected from CR⁵ and N; Y₁is selected from CR⁶ and N; Y₂ is selected from CR⁷ and N; and each R⁴,R⁵, R⁶ and R⁷ is independently selected from hydrogen, halogen and C₁-C₃alkyl.
 6. The compound of claim 5 having Formula 1.4:


7. The compound of claim 5 that is4-(2-(methylthio)pyrimidin-4-yl)pyridin-2(1H)-one.
 8. A compound ofFormula 10.2:

wherein: X₁ is selected from CH and N; X₂ is selected from CR⁵ and N; Y₁is selected from CR⁶ and N; Y₂ is selected from CR⁷ and N; R² isselected from (a) hydrogen, (b) C₁-C₆ alkyl optionally substituted withone or more groups selected from OR^(f), oxo, NH₂, NH(C₁-C₃ alkyl) andN(C₁-C₃ alkyl)₂, (c) C₁-C₆ alkenyl optionally substituted with one ormore groups selected from OR^(f), oxo, NH₂, NH(C₁-C₃ alkyl) and N(C₁-C₃alkyl)₂, (d) C₁-C₆ alkynyl optionally substituted with one or moregroups selected from OR^(f), oxo, NH₂, NH(C₁-C₃ alkyl) and N(C₁-C₃alkyl)₂, (e) C₃-C₆ cycloalkyl optionally substituted with one or moregroups selected from OR^(f) and R^(g), (f) phenyl optionally substitutedwith one or more groups selected from OR^(f) and R^(g), (g) a 3 to 7membered heterocycle optionally substituted with one or more groupsselected from OR^(f) and R^(g), and (h) a 5 to 6 membered heteroaryloptionally substituted with one or more groups selected from OR^(f) andR^(g); R³ is selected from (a) (CR^(h)R^(i))_(x)-phenyl, wherein thephenyl may be optionally substituted with one or more R^(j) groups, (b)(CR^(h)R^(i))_(x)-(5 to 6 membered heteroaryl), wherein the heteroarylmay be optionally substituted with one or more R^(j) groups, (c)(CR^(h)R^(i))_(x)-(9 to 10 membered bicyclic heterocycle), wherein theheterocycle may be optionally substituted with one or more R^(j) groups,and (d) (CR^(h)R^(i))_(x)-(9 to 10 membered bicyclic heteroaryl),wherein the heteroaryl may be optionally substituted with one or moreR^(j) groups; each R⁴, R⁵, R⁶ and R⁷ is independently selected fromhydrogen, halogen and C₁-C₃ alkyl; each R^(f) is independently selectedfrom hydrogen and C₁-C₆ alkyl optionally substituted with one or moregroups selected from oxo, NH₂, NH(C₁-C₃ alkyl) and N(C₁-C₃ alkyl)₂; eachR^(g) is C₁-C₆ alkyl; R^(h) and R^(i) are independently selected fromhydrogen, OR^(k) and C₁-C₆ alkyl optionally substituted with OR^(m);each R^(j) is independently selected from halogen, CN, cyclopropyl,C₁-C₆ alkyl optionally substituted with halogen, and C₁-C₆ alkoxyoptionally substituted with halogen; R^(k) and R^(m) are independentlyhydrogen or C₁-C₃ alkyl; and x is 0 or
 1. 9. The compound of claim 8having the structure 3.2:


10. The compound selected from:(R)-2-(tert-butyldimethylsilyloxy)-1-(4-chloro-3-fluorophenyl)ethylmethanesulfonate;(R)-2-((tert-butyldimethylsilyl)oxy)-1-(3-chloro-4-fluorophenyl)ethylmethanesulfonate;2-((tert-butyldimethylsilyl)oxy)-1-(3-chloro-4-fluorophenyl)ethylmethanesulfonate; and2-(tert-butyldimethylsilyloxy)-1-(4-chloro-3-fluorophenyl)ethylmethanesulfonate.
 11. A compound that is(S)-3-(tert-butyldimethylsilyloxy)-1-(4-chloro-3-fluorophenyl)propylmethanesulfonate.
 12. A compound of Formula 10.6:

wherein: X₁ is selected from CH and N; X₂ is selected from CR⁵ and N; Y₁is selected from CR⁶ and N; Y₂ is selected from CR⁷ and N; R² isselected from (a) hydrogen, (b) C₁-C₆ alkyl optionally substituted withone or more groups selected from OR^(f), oxo, NH₂, NH(C₁-C₃ alkyl) andN(C₁-C₃ alkyl)₂, (c) C₁-C₆ alkenyl optionally substituted with one ormore groups selected from OR^(f), oxo NH₂, NH(C₁-C₃ alkyl) and N(C₁-C₃alkyl)₂, (d) C₁-C₆ alkynyl optionally substituted with one or moregroups selected from OR^(f), oxo, NH₂, NH(C₁-C₃ alkyl) and N(C₁-C₃alkyl)₂, (e) C₃-C₆ cycloalkyl optionally substituted with one or moregroups selected from OR^(f) and R^(g), (f) phenyl optionally substitutedwith one or more groups selected from OR^(f) and R^(g), (g) a 3 to 7membered heterocycle optionally substituted with one or more groupsselected from OR^(f) and R^(g), and (h) a 5 to 6 membered heteroaryloptionally substituted with one or more groups selected from OR^(f) andR^(g); R³ is selected from (a) (CR^(h)R^(i))_(x)-phenyl, wherein thephenyl may be optionally substituted with one or more R^(j) groups, (b)(CR^(h)R^(i))_(x)-(5 to 6 membered heteroaryl), wherein the heteroarylmay be optionally substituted with one or more R^(j) groups, (c)(CR^(h)R^(i))_(x)-(9 to 10 membered bicyclic heterocycle), wherein theheterocycle may be optionally substituted with one or more R^(j) groups,and (d) (CR^(h)R^(i))_(x)-(9 to 10 membered bicyclic heteroaryl),wherein the heteroaryl may be optionally substituted with one or moreR^(j) groups; each R⁴, R⁵, R⁶ and R⁷ is independently selected fromhydrogen, halogen and C₁-C₃ alkyl; each R^(f) is independently selectedfrom hydrogen and C₁-C₆ alkyl optionally substituted with one or moregroups selected from oxo, NH₂, NH(C₁-C₃ alkyl) and N(C₁-C₃ alkyl)₂; eachR^(g) is C₁-C₆ alkyl; R^(h) and R^(i) are independently selected fromhydrogen, OR^(k) and C₁-C₆ alkyl optionally substituted with OR^(m);each R^(j) is independently selected from halogen, CN, cyclopropyl,C₁-C₆ alkyl optionally substituted with halogen, and C₁-C₆ alkoxyoptionally substituted with halogen; R^(k) and R^(m) are independentlyhydrogen or C₁-C₃ alkyl; and x is 0 or
 1. 13. The compound of claim 12having the structure 8.1:


14. A compound that is(S)-1-(2-(tert-butyldimethylsilyloxy)-1-(4-chloro-3-fluorophenyl)ethyl)-4-(2-(methylsulfonyl)pyrimidin-4-yl)pyridin-2(1H)-one.15. A compound of Formula 10.8:

wherein: X₁ is selected from CH and N; X₂ is selected from CR⁵ and N; Y₁is selected from CR⁶ and N; Y₂ is selected from CR⁷ and N; R¹ isselected from (a) C₁-C₆ alkyl optionally substituted with one or moregroups independently selected from halogen, OR^(a), NR^(b)R^(c), oxo,CN, C₃-C₆ cycloalkyl and a 3 to 7 membered heterocycle, (b) C₃-C₇cycloalkyl optionally substituted with one or more groups independentlyselected from halogen, OR^(a), CN and C₁-C₃ alkyl optionally substitutedwith one or more groups independently selected from halogen and OR^(d),(c) phenyl optionally substituted with one or more groups independentlyselected from halogen, OR^(a), CN, C₃-C₆ cycloalkyl and C₁-C₃ alkyloptionally substituted with one or more groups independently selectedfrom halogen and OR^(d), (d) a 3 to 7 membered saturated or partiallyunsaturated heterocycle optionally substituted with one or more groupsindependently selected from halogen, OR^(a), oxo, CN, C₃-C₆ cycloalkyland C₁-C₃ alkyl optionally substituted with one or more groupsindependently selected from halogen and OR^(d), (e) a 5 to 6 memberedheteroaryl optionally substituted with one or more groups independentlyselected from halogen, OR^(e), oxide, CN, C₃-C₆ cycloalkyl and C₁-C₃alkyl optionally substituted with one or more groups independentlyselected from halogen, oxo and OR^(d), and (f) a 7 to 10 memberedbicyclic heterocycle optionally substituted with one or more groupsindependently selected from halogen, OR^(a), oxo, CN, C₃-C₆ cycloalkyland C₁-C₃ alkyl optionally substituted with one or more groupsindependently selected from halogen and OR^(d); each R⁴, R⁵, R⁶ and R⁷is independently selected from hydrogen, halogen and C₁-C₃ alkyl; andeach R^(a), R^(b), R^(c), R^(d) and R^(e) is independently selected fromhydrogen and C₁-C₆ alkyl.
 16. The compound of claim 15 having thestructure 9.4:


17. A process for preparing a compound of Formula 10.1, comprising: (a)coupling a compound having the structure:

with a compound having the structure:

to prepare a compound having the structure:

and (b) hydrolyzing the compound having the structure:

to prepare a compound of Formula 10.1:

wherein: X₁ is selected from CH and N; X₂ is selected from CR⁵ and N; Y₁is selected from CR⁶ and N; Y₂ is selected from CR⁷ and N; each R⁴, R⁵,R⁶ and R⁷ is independently selected from hydrogen, halogen and C₁-C₃alkyl; and R¹¹ is selected from Cl, Br and I.
 18. The process of claim17 wherein a compound of Formula 1.4 is prepared, comprising: (a)coupling a compound of Formula 1.1:

with a compound of Formula 1.2:

to prepare a compound of Formula 1.3:

and (b) hydrolyzing the compound of Formula 1.3 to prepare a compound ofFormula 1.4:


19. A process for preparing a compound of Formula 10.2, comprising:reacting a compound of Formula 10.1:

with a compound having the structure:

to prepare a compound of Formula 10.2:

wherein: X₁ is selected from CH and N; X₂ is selected from CR⁵ and N; Y₁is selected from CR⁶ and N; Y₂ is selected from CR⁷ and N; R² isselected from (a) hydrogen, (b) C₁-C₆ alkyl optionally substituted withone or more groups selected from OR^(f), oxo, NH₂, NH(C₁-C₃ alkyl) andN(C₁-C₃ alkyl)₂, (c) C₁-C₆ alkenyl optionally substituted with one ormore groups selected from OR^(f), oxo, NH₂, NH(C₁-C₃ alkyl) and N(C₁-C₃alkyl)₂, (d) C₁-C₆ alkynyl optionally substituted with one or moregroups selected from OR^(f), oxo, NH₂, NH(C₁-C₃ alkyl) and N(C₁-C₃alkyl)₂, (e) C₃-C₆ cycloalkyl optionally substituted with one or moregroups selected from OR^(f) and R^(g), (f) phenyl optionally substitutedwith one or more groups selected from OR^(f) and R^(g), (g) a 3 to 7membered heterocycle optionally substituted with one or more groupsselected from OR^(r) and R^(g), and (h) a 5 to 6 membered heteroaryloptionally substituted with one or more groups selected from OR^(f) andR^(g); R³ is selected from (a) (CR^(h)R^(i))_(x)-phenyl, wherein thephenyl may be optionally substituted with one or more R^(j) groups, (b)(CR^(h)R^(i))_(x)-(5 to 6 membered heteroaryl), wherein the heteroarylmay be optionally substituted with one or more R^(j) groups, (c)(CR^(h)R^(i))_(x)-(9 to 10 membered bicyclic heterocycle), wherein theheterocycle may be optionally substituted with one or more R^(j) groups,and (d) (CR^(h)R^(i))_(x)-(9 to 10 membered bicyclic heteroaryl),wherein the heteroaryl may be optionally substituted with one or moreR^(j) groups; each R⁴, R⁵, R⁶ and R⁷ is independently selected fromhydrogen, halogen and C₁-C₃ alkyl; each R^(f) is independently selectedfrom hydrogen and C₁-C₆ alkyl optionally substituted with one or moregroups selected from oxo, NH₂, NH(C₁-C₃ alkyl) and N(C₁-C₃ alkyl)₂; eachR^(g) is C₁-C₆ alkyl; R^(h) and R^(i) are independently selected fromhydrogen, OR^(k) and C₁-C₆ alkyl optionally substituted with OR^(m);each R^(j) is independently selected from halogen, CN, cyclopropyl,C₁-C₆ alkyl optionally substituted with halogen, and C₁-C₆ alkoxyoptionally substituted with halogen; R^(k) and R^(m) are independentlyhydrogen or C₁-C₃ alkyl; x is 0 or 1; and X is Cl, Br, I, OMs or OTf.20. The process of claim 19, wherein a compound of Formula 3.2 isprepared, comprising: reacting a compound of Formula 1.4:

with a compound of Formula 3.1:

to prepare a compound of Formula 3.2:


21. A process for preparing a compound of Formula 10.2, comprising:reacting a compound of Formula 10.1:

with a compound having the structure:

to prepare a compound of Formula 10.2:

wherein: X₁ is selected from CH and N; X₂ is selected from CR⁵ and N; Y₁is selected from CR⁶ and N; Y₂ is selected from CR⁷ and N; R² isselected from (a) hydrogen, (b) C₁-C₆ alkyl optionally substituted withone or more groups selected from OR^(f), oxo, NH₂, NH(C₁-C₃ alkyl) andN(C₁-C₃ alkyl)₂, (c) C₁-C₆ alkenyl optionally substituted with one ormore groups selected from OR^(f), oxo, NH₂, NH(C₁-C₃ alkyl) and N(C₁-C₃alkyl)₂, (d) C₁-C₆ alkynyl optionally substituted with one or moregroups selected from OR^(f), oxo, NH₂, NH(C₁-C₃ alkyl) and N(C₁-C₃alkyl)₂, (e) C₃-C₆ cycloalkyl optionally substituted with one or moregroups selected from OR^(f) and R^(g), (f) phenyl optionally substitutedwith one or more groups selected from OR^(f) and R^(g), (g) a 3 to 7membered heterocycle optionally substituted with one or more groupsselected from OR^(f) and R^(g), and (h) a 5 to 6 membered heteroaryloptionally substituted with one or more groups selected from OR^(f) andR^(g); R³ is selected from (a) (CR^(h)R^(i))_(x)-phenyl, wherein thephenyl may be optionally substituted with one or more R^(j) groups, (b)(CR^(h)R^(i))_(x)-(5 to 6 membered heteroaryl), wherein the heteroarylmay be optionally substituted with one or more R^(j) groups, (c)(CR^(h)R^(i))_(x)-(9 to 10 membered bicyclic heterocycle), wherein theheterocycle may be optionally substituted with one or more R^(j) groups,and (d) (CR^(h)R^(i))_(x)-(9 to 10 membered bicyclic heteroaryl),wherein the heteroaryl may be optionally substituted with one or moreR^(j) groups; each R⁴, R⁵, R⁶ and R⁷ is independently selected fromhydrogen, halogen and C₁-C₃ alkyl; each R^(f) is independently selectedfrom hydrogen and C₁-C₆ alkyl optionally substituted with one or moregroups selected from oxo, NH₂, NH(C₁-C₃ alkyl) and N(C₁-C₃ alkyl)₂; eachR^(g) is C₁-C₆ alkyl; R^(h) and R^(i) are independently selected fromhydrogen, OR^(k) and C₁-C₆ alkyl optionally substituted with OR^(m);each R^(j) is independently selected from halogen, CN, cyclopropyl,C₁-C₆ alkyl optionally substituted with halogen, and C₁-C₆ alkoxyoptionally substituted with halogen; R^(k) and R^(m) are independentlyhydrogen or C₁-C₃ alkyl; and x is 0 or
 1. 22. The process of claim 21,wherein a compound of Formula 3.2 is prepared, comprising: reacting acompound of Formula 1.4:

with a compound of Formula 4.1:

to prepare a compound of Formula 3.2:


23. A process for preparing a compound of Formula 10.6, comprising:oxidizing a compound of Formula 10.2:

to prepare a compound of Formula 10.6:

wherein: X₁ is selected from CH and N; X₂ is selected from CR⁵ and N; Y₁is selected from CR⁶ and N; Y₂ is selected from CR⁷ and N; R² isselected from (a) hydrogen, (b) C₁-C₆ alkyl optionally substituted withone or more groups selected from OR^(f), oxo, NH₂, NH(C₁-C₃ alkyl) andN(C₁-C₃ alkyl)₂, (c) C₁-C₆ alkenyl optionally substituted with one ormore groups selected from OR^(f), oxo, NH₂, NH(C₁-C₃ alkyl) and N(C₁-C₃alkyl)₂, (d) C₁-C₆ alkynyl optionally substituted with one or moregroups selected from OR^(f), oxo, NH₂, NH(C₁-C₃ alkyl) and N(C₁-C₃alkyl)₂, (e) C₃-C₆ cycloalkyl optionally substituted with one or moregroups selected from OR^(f) and R^(g), (f) phenyl optionally substitutedwith one or more groups selected from OR^(f) and R^(g), (g) a 3 to 7membered heterocycle optionally substituted with one or more groupsselected from OR^(f) and R^(g), and (h) a 5 to 6 membered heteroaryloptionally substituted with one or more groups selected from OR^(f) andR^(g); R³ is selected from (a) (CR^(h)R^(i))_(x)-phenyl, wherein thephenyl may be optionally substituted with one or more R^(j) groups, (b)(CR^(h)R^(i))_(x)-(5 to 6 membered heteroaryl), wherein the heteroarylmay be optionally substituted with one or more R^(j) groups, (c)(CR^(h)R^(i))_(x)-(9 to 10 membered bicyclic heterocycle), wherein theheterocycle may be optionally substituted with one or more R^(j) groups,and (d) (CR^(h)R^(i))_(x)-(9 to 10 membered bicyclic heteroaryl),wherein the heteroaryl may be optionally substituted with one or moreR^(j) groups; each R⁴, R⁵, R⁶ and R⁷ is independently selected fromhydrogen, halogen and C₁-C₃ alkyl; each R^(f) is independently selectedfrom hydrogen and C₁-C₆ alkyl optionally substituted with one or moregroups selected from oxo, NH₂, NH(C₁-C₃ alkyl) and N(C₁-C₃ alkyl)₂; eachR^(g) is C₁-C₆ alkyl; R^(h) and R^(i) are independently selected fromhydrogen, OR^(k) and C₁-C₆ alkyl optionally substituted with OR^(m);each R^(j) is independently selected from halogen, CN, cyclopropyl,C₁-C₆ alkyl optionally substituted with halogen, and C₁-C₆ alkoxyoptionally substituted with halogen; R^(k) and R^(m) are independentlyhydrogen or C₁-C₃ alkyl; and x is 0 or
 1. 24. The process of claim 23,wherein a compound of Formula 8.1 is prepared, comprising: oxidizing acompound of Formula 3.2:

to prepare a compound of Formula 8.1:


25. A process for preparing a compound of Formula 10.8, comprising: (a)coupling a compound having the structure:

with a compound having the structure:

to prepare a compound having the structure:

(b) reacting the compound having the structure:

with NH₂R¹ to prepare a compound having the structure:

and (c) hydrolyzing the compound having the structure:

to prepare a compound of Formula 10.8:

wherein: X₁ is selected from CH and N; X₂ is selected from CR⁵ and N; Y₁is selected from CR⁶ and N; Y₂ is selected from CR⁷ and N; R¹ isselected from (a) C₁-C₆ alkyl optionally substituted with one or moregroups independently selected from halogen, OR^(a), NR^(b)R^(c), oxo,CN, C₃-C₆ cycloalkyl and a 3 to 7 membered heterocycle, (b) C₃-C₇cycloalkyl optionally substituted with one or more groups independentlyselected from halogen, OR^(a), CN and C₁-C₃ alkyl optionally substitutedwith one or more groups independently selected from halogen and OR^(d),(c) phenyl optionally substituted with one or more groups independentlyselected from halogen, OR^(a), CN, C₃-C₆ cycloalkyl and C₁-C₃ alkyloptionally substituted with one or more groups independently selectedfrom halogen and OR^(d), (d) a 3 to 7 membered saturated or partiallyunsaturated heterocycle optionally substituted with one or more groupsindependently selected from halogen, OR^(a), oxo, CN, C₃-C₆ cycloalkyland C₁-C₃ alkyl optionally substituted with one or more groupsindependently selected from halogen and OR^(d), (e) a 5 to 6 memberedheteroaryl optionally substituted with one or more groups independentlyselected from halogen, OR^(e), oxide, CN, C₃-C₆ cycloalkyl and C₁-C₃alkyl optionally substituted with one or more groups independentlyselected from halogen, oxo and OR^(d), and (f) a 7 to 10 memberedbicyclic heterocycle optionally substituted with one or more groupsindependently selected from halogen, OR^(a), oxo, CN, C₃-C₆ cycloalkyland C₁-C₃ alkyl optionally substituted with one or more groupsindependently selected from halogen and OR^(d); each R⁴, R⁵, R⁶ and R⁷is independently selected from hydrogen, halogen and C₁-C₃ alkyl; andeach R^(a), R^(b), R^(c), R^(d), and R^(e) is independently selectedfrom hydrogen and C₁-C₆ alkyl.
 26. The process of claim 25, wherein acompound of Formula 9.4 is prepared, comprising: (a) coupling a compoundof Formula 9.1:

with a compound of Formula 1.2:

to prepare a compound of Formula 9.2:

(b) reacting the compound of Formula 9.2 with NH₂R¹ to prepare acompound of Formula 9.3:

and (c) hydrolyzing the compound of Formula 9.3 to prepare a compound ofFormula 9.4:


27. A process for preparing compounds of Formula I, comprising: reactinga compound of Formula 10.6:

with NH₂R¹ to prepare a compound of Formula I:

wherein: X₁ is selected from CH and N; X₂ is selected from CR⁵ and N; Y₁is selected from CR⁶ and N; Y₂ is selected from CR⁷ and N; R¹ isselected from (a) C₁-C₆ alkyl optionally substituted with one or moregroups independently selected from halogen, OR^(a), NR^(b)R^(c), oxo,CN, C₃-C₆ cycloalkyl and a 3 to 7 membered heterocycle, (b) C₃-C₇cycloalkyl optionally substituted with one or more groups independentlyselected from halogen, OR^(a), CN and C₁-C₃ alkyl optionally substitutedwith one or more groups independently selected from halogen and OR^(d),(c) phenyl optionally substituted with one or more groups independentlyselected from halogen, OR^(a), CN, C₃-C₆ cycloalkyl and C₁-C₃ alkyloptionally substituted with one or more groups independently selectedfrom halogen and OR^(d), (d) a 3 to 7 membered saturated or partiallyunsaturated heterocycle optionally substituted with one or more groupsindependently selected from halogen, OR^(a), oxo, CN, C₃-C₆ cycloalkyland C₁-C₃ alkyl optionally substituted with one or more groupsindependently selected from halogen and OR^(d), (e) a 5 to 6 memberedheteroaryl optionally substituted with one or more groups independentlyselected from halogen, OR^(e), oxide, CN, C₃-C₆ cycloalkyl and C₁-C₃alkyl optionally substituted with one or more groups independentlyselected from halogen, oxo and OR^(d), and (f) a 7 to 10 memberedbicyclic heterocycle optionally substituted with one or more groupsindependently selected from halogen, OR^(a), oxo, CN, C₃-C₆ cycloalkyland C₁-C₃ alkyl optionally substituted with one or more groupsindependently selected from halogen and OR^(d); R² is selected from (a)hydrogen, (b) C₁-C₆ alkyl optionally substituted with one or more groupsselected from OR^(f), oxo, NH₂, NH(C₁-C₃ alkyl) and N(C₁-C₃ alkyl)₂, (c)C₁-C₆ alkenyl optionally substituted with one or more groups selectedfrom OR^(f), oxo, NH₂, NH(C₁-C₃ alkyl) and N(C₁-C₃ alkyl)₂, (d) C₁-C₆alkynyl optionally substituted with one or more groups selected fromOR^(f), oxo, NH₂, NH(C₁-C₃ alkyl) and N(C₁-C₃ alkyl)₂, (e) C₃-C₆cycloalkyl optionally substituted with one or more groups selected fromOR^(f) and R^(g), (f) phenyl optionally substituted with one or moregroups selected from OR^(f) and R^(g), (g) a 3 to 7 membered heterocycleoptionally substituted with one or more groups selected from OR^(f) andR^(g), and (h) a 5 to 6 membered heteroaryl optionally substituted withone or more groups selected from OR^(f) and R^(g); R³ is selected from(a) (CR^(h)R^(i))_(x)-phenyl, wherein the phenyl may be optionallysubstituted with one or more R^(j) groups, (b) (CR^(h)R^(i))_(x)-(5 to 6membered heteroaryl), wherein the heteroaryl may be optionallysubstituted with one or more R^(j) groups, (c) (CR^(h)R^(i))_(x)-(9 to10 membered bicyclic heterocycle), wherein the heterocycle may beoptionally substituted with one or more R^(j) groups, and (d)(CR^(h)R^(i))_(x)-(9 to 10 membered bicyclic heteroaryl), wherein theheteroaryl may be optionally substituted with one or more R^(j) groups;each R⁴, R⁵, R⁶ and R⁷ is independently selected from hydrogen, halogenand C₁-C₃ alkyl; each R^(a), R^(b), R^(c), R^(d) and R^(e) areindependently selected from hydrogen and C₁-C₆ alkyl; R^(f) is selectedfrom hydrogen and C₁-C₆ alkyl optionally substituted with one or moregroups selected from oxo, NH₂, NH(C₁-C₃ alkyl) and N(C₁-C₃ alkyl)₂; eachR^(g) is C₁-C₆ alkyl; R^(h) and R^(i) are independently selected fromhydrogen, OR^(k) and C₁-C₆ alkyl optionally substituted with OR^(m);each R^(j) is independently selected from halogen, CN, cyclopropyl,C₁-C₆ alkyl optionally substituted with halogen, and C₁-C₆ alkoxyoptionally substituted with halogen; R^(k) and R^(m) are independentlyhydrogen or C₁-C₃ alkyl; and x is 0 or
 1. 28. A process for preparing acompound of Formula I, comprising: reacting a compound of Formula 10.6:

with NH₂R¹ to prepare a compound of Formula I:

wherein: X₁ is selected from CH and N; X₂ is selected from CR⁵ and N; Y₁is selected from CR⁶ and N; Y₂ is selected from CR⁷ and N; R¹ isselected from (a) C₁-C₆ alkyl optionally substituted with one or moregroups independently selected from halogen, OR^(a), NR^(b)R^(c), oxo,CN, C₃-C₆ cycloalkyl and a 3 to 7 membered heterocycle, (b) C₃-C₇cycloalkyl optionally substituted with one or more groups independentlyselected from halogen, OR^(a), CN and C₁-C₃ alkyl optionally substitutedwith one or more groups independently selected from halogen and OR^(d),(c) phenyl optionally substituted with one or more groups independentlyselected from halogen, OR^(a), CN, C₃-C₆ cycloalkyl and C₁-C₃ alkyloptionally substituted with one or more groups independently selectedfrom halogen and OR^(d), (d) a 3 to 7 membered saturated or partiallyunsaturated heterocycle optionally substituted with one or more groupsindependently selected from halogen, OR^(a), oxo, CN, C₃-C₆ cycloalkyland C₁-C₃ alkyl optionally substituted with one or more groupsindependently selected from halogen and OR^(d), (e) a 5 to 6 memberedheteroaryl optionally substituted with one or more groups independentlyselected from halogen, OR^(e), oxide, CN, C₃-C₆ cycloalkyl and C₁-C₃alkyl optionally substituted with one or more groups independentlyselected from halogen, oxo and OR^(d), and (f) a 7 to 10 memberedbicyclic heterocycle optionally substituted with one or more groupsindependently selected from halogen, OR^(a), oxo, CN, C₃-C₆ cycloalkyland C₁-C₃ alkyl optionally substituted with one or more groupsindependently selected from halogen and OR^(d); R² is selected from (a)hydrogen, (b) C₁-C₆ alkyl optionally substituted with one or more groupsselected from OR^(f), oxo, NH₂, NH(C₁-C₃ alkyl) and N(C₁-C₃ alkyl)₂, (c)C₁-C₆ alkenyl optionally substituted with one or more groups selectedfrom OR^(f), oxo, NH₂, NH(C₁-C₃ alkyl) and N(C₁-C₃ alkyl)₂, (d) C₁-C₆alkynyl optionally substituted with one or more groups selected fromOR^(f), oxo, NH₂, NH(C₁-C₃ alkyl) and N(C₁-C₃ alkyl)₂, (e) C₃-C₆cycloalkyl optionally substituted with one or more groups selected fromOR^(f) and R^(g), (f) phenyl optionally substituted with one or moregroups selected from OR^(f) and R^(g), (g) a 3 to 7 membered heterocycleoptionally substituted with one or more groups selected from OR^(f) andR^(g), and (h) a 5 to 6 membered heteroaryl optionally substituted withone or more groups selected from OR^(f) and R^(g); R³ is selected from(a) (CR^(h)R^(i))_(x)-phenyl, wherein the phenyl may be optionallysubstituted with one or more R^(j) groups, (b) (CR^(h)R^(i))_(x)-(5 to 6membered heteroaryl), wherein the heteroaryl may be optionallysubstituted with one or more R^(j) groups, (c) (CR^(h)R^(i))_(x)-(9 to10 membered bicyclic heterocycle), wherein the heterocycle may beoptionally substituted with one or more R^(j) groups, and (d)(CR^(h)R^(i))_(x)-(9 to 10 membered bicyclic heteroaryl), wherein theheteroaryl may be optionally substituted with one or more R^(j) groups;each R⁴, R⁵, R⁶ and R⁷ is independently selected from hydrogen, halogenand C₁-C₃ alkyl; each R^(a), R^(b), R^(c), Rd and R^(e) is independentlyselected from hydrogen and C₁-C₆ alkyl; R^(f) is selected from hydrogenand C₁-C₆ alkyl optionally substituted with one or more groups selectedfrom oxo, NH₂, NH(C₁-C₃ alkyl) and N(C₁-C₃ alkyl)₂; each R^(g) is C₁-C₆alkyl; R^(h) and R^(i) are independently selected from hydrogen, OR^(k)and C₁-C₆ alkyl optionally substituted with OR^(m); each R^(j) isindependently selected from halogen, CN, cyclopropyl, C₁-C₆ alkyloptionally substituted with halogen, and C₁-C₆ alkoxy optionallysubstituted with halogen; R^(k) and R^(m) are independently hydrogen orC₁-C₃ alkyl; and x is 0 or
 1. 29. A process for preparing a compound ofFormula I, comprising: reacting a compound of Formula 10.8:

with a compound having the structure:

to prepare a compound of Formula I:

wherein: X₁ is selected from CH and N; X₂ is selected from CR⁵ and N; Y₁is selected from CR⁶ and N; Y₂ is selected from CR⁷ and N; R¹ isselected from (a) C₁-C₆ alkyl optionally substituted with one or moregroups independently selected from halogen, OR^(a), NR^(b)R^(c), oxo,CN, C₃-C₆ cycloalkyl and a 3 to 7 membered heterocycle, (b) C₃-C₇cycloalkyl optionally substituted with one or more groups independentlyselected from halogen, OR^(a), CN and C₁-C₃ alkyl optionally substitutedwith one or more groups independently selected from halogen and OR^(d),(c) phenyl optionally substituted with one or more groups independentlyselected from halogen, OR^(a), CN, C₃-C₆ cycloalkyl and C₁-C₃ alkyloptionally substituted with one or more groups independently selectedfrom halogen and OR^(d), (d) a 3 to 7 membered saturated or partiallyunsaturated heterocycle optionally substituted with one or more groupsindependently selected from halogen, OR^(a), oxo, CN, C₃-C₆ cycloalkyland C₁-C₃ alkyl optionally substituted with one or more groupsindependently selected from halogen and OR^(d), (e) a 5 to 6 memberedheteroaryl optionally substituted with one or more groups independentlyselected from halogen, OR^(e), oxide, CN, C₃-C₆ cycloalkyl and C₁-C₃alkyl optionally substituted with one or more groups independentlyselected from halogen, oxo and OR^(d), and (f) a 7 to 10 memberedbicyclic heterocycle optionally substituted with one or more groupsindependently selected from halogen, OR^(a), oxo, CN, C₃-C₆ cycloalkyland C₁-C₃ alkyl optionally substituted with one or more groupsindependently selected from halogen and OR^(d); R² is selected from (a)hydrogen, (b) C₁-C₆ alkyl optionally substituted with one or more groupsselected from OR^(f), oxo, NH₂, NH(C₁-C₃ alkyl) and N(C₁-C₃ alkyl)₂, (c)C₁-C₆ alkenyl optionally substituted with one or more groups selectedfrom OR^(f), oxo, NH₂, NH(C₁-C₃ alkyl) and N(C₁-C₃ alkyl)₂, (d) C₁-C₆alkynyl optionally substituted with one or more groups selected fromOR^(f), oxo, NH₂, NH(C₁-C₃ alkyl) and N(C₁-C₃ alkyl)₂, (e) C₃-C₆cycloalkyl optionally substituted with one or more groups selected fromOR^(f) and R^(g), (f) phenyl optionally substituted with one or moregroups selected from OR^(f) and R^(g), (g) a 3 to 7 membered heterocycleoptionally substituted with one or more groups selected from OR^(f) andR^(g), and (h) a 5 to 6 membered heteroaryl optionally substituted withone or more groups selected from OR^(f) and R^(g); R³ is selected from(a) (CR^(h)R^(i))_(x)-phenyl, wherein the phenyl may be optionallysubstituted with one or more R^(j) groups, (b) (CR^(h)R^(i))_(x)-(5 to 6membered heteroaryl), wherein the heteroaryl may be optionallysubstituted with one or more R^(j) groups, (c) (CR^(h)R^(i))_(x)-(9 to10 membered bicyclic heterocycle), wherein the heterocycle may beoptionally substituted with one or more R^(j) groups, and (d)(CR^(h)R^(i))_(x)-(9 to 10 membered bicyclic heteroaryl), wherein theheteroaryl may be optionally substituted with one or more R^(j) groups;each R⁴, R⁵, R⁶ and R⁷ is independently selected from hydrogen, halogenand C₁-C₃ alkyl; each R^(a), R^(b), R^(c), R^(d) and Re areindependently selected from hydrogen and C₁-C₆ alkyl; R^(f) is selectedfrom hydrogen and C₁-C₆ alkyl optionally substituted with one or moregroups selected from oxo, NH₂, NH(C₁-C₃ alkyl) and N(C₁-C₃ alkyl)₂; eachR^(g) is C₁-C₆ alkyl; R^(h) and R^(i) are independently selected fromhydrogen, OR^(k) and C₁-C₆ alkyl optionally substituted with OR^(m);each R^(j) is independently selected from halogen, CN, cyclopropyl,C₁-C₆ alkyl optionally substituted with halogen, and C₁-C₆ alkoxyoptionally substituted with halogen; R^(k) and R^(m) are independentlyhydrogen or C₁-C₃ alkyl; x is 0 or 1; and X is Cl, Br, I, OMs or OTf.30. A compound selected from Formula XI:

wherein: X₁ is selected from CH and N; X₂ is selected from CR⁵ and N; Y₁is selected from CR⁶ and N; Y₂ is selected from CR⁷ and N; R¹ isselected from (a) C₁-C₆ alkyl optionally substituted with one or moregroups independently selected from halogen, OR^(a), NR^(b)R^(c), oxo,CN, C₃-C₆ cycloalkyl and a 3 to 7 membered heterocycle, (b) C₃-C₇cycloalkyl optionally substituted with one or more groups independentlyselected from halogen, OR^(a), CN and C₁-C₃ alkyl optionally substitutedwith one or more groups independently selected from halogen and OR^(d),(c) phenyl optionally substituted with one or more groups independentlyselected from halogen, OR^(a), CN, C₃-C₆ cycloalkyl and C₁-C₃ alkyloptionally substituted with one or more groups independently selectedfrom halogen and OR^(d), (d) a 3 to 7 membered saturated or partiallyunsaturated heterocycle optionally substituted with one or more groupsindependently selected from halogen, OR^(a), oxo, CN, C₃-C₆ cycloalkyland C₁-C₃ alkyl optionally substituted with one or more groupsindependently selected from halogen and OR^(d), (e) a 5 to 6 memberedheteroaryl optionally substituted with one or more groups independentlyselected from halogen, OR^(e), oxide, CN, C₃-C₆ cycloalkyl and C₁-C₃alkyl optionally substituted with one or more groups independentlyselected from halogen, oxo and OR^(d), and (f) a 7 to 10 memberedbicyclic heterocycle optionally substituted with one or more groupsindependently selected from halogen, OR^(a), oxo, CN, C₃-C₆ cycloalkyland C₁-C₃ alkyl optionally substituted with one or more groupsindependently selected from halogen and OR^(d); R³ is selected from (a)(CR^(h)R^(i))_(x)-phenyl, wherein the phenyl may be optionallysubstituted with one or more R^(j) groups, (b) (CR^(h)R^(i))_(x)-(5 to 6membered heteroaryl), wherein the heteroaryl may be optionallysubstituted with one or more R^(j) groups, (c) (CR^(h)R^(i))_(x)-(9 to10 membered bicyclic heterocycle), wherein the heterocycle may beoptionally substituted with one or more R^(j) groups, and (d)(CR^(h)R^(i))_(x)-(9 to 10 membered bicyclic heteroaryl), wherein theheteroaryl may be optionally substituted with one or more R^(j) groups;R^(pd) is OP(═O)(OH)₂ or CH₂OP(═O)(OH)₂; each R⁴, R⁵, R⁶ and R⁷ isindependently selected from hydrogen, halogen and C₁-C₃ alkyl; eachR^(a), R^(b), R^(c), R^(d) and R^(e) are independently selected fromhydrogen and C₁-C₆ alkyl; R^(h) and R^(i) are independently selectedfrom hydrogen, OR^(k) and C₁-C₆ alkyl optionally substituted withOR^(m); each R^(j) is independently selected from halogen, CN,cyclopropyl, C₁-C₆ alkyl optionally substituted with halogen, and C₁-C₆alkoxy optionally substituted with halogen; R^(k) and R^(m) areindependently hydrogen or C₁-C₃ alkyl; and x is 0 or
 1. 31. The compoundof claim 30, wherein the compound is selected from:(S)-2-(4-chloro-3-fluorophenyl)-2-(2-oxo-4-(2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)pyridin-1(2H)-yl)ethyl dihydrogen phosphate; and(S)-(2-(4-chloro-3-fluorophenyl)-2-(2-oxo-4-(2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)pyridin-1(2H)-yl)ethoxy)methyl dihydrogen phosphate.